Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 1, pp. S394-S418 © Pleiades Publishing, Ltd., 2026.

Russian Text © The Author(s), 2026, published in Uspekhi Biologicheskoi Khimii, 2026, Vol. 66, pp. 549-580.

S394

REVIEW

Thyroid Peroxidase Gene Mutations

Associated with Thyroid Disorders

Alexander V. Zubkov

1,a

* and Ludmila G. Butova

Mechnikov Research Institute of Vaccine and Sera, 105064 Moscow, Russia

e-mail: alex_zubkov@list.ru

Received August 21, 2025

Revised December 5, 2025

Accepted December 9, 2025

Abstract— The TPO gene belongs to the group of genes responsible for the biosynthesis of thyroid hormones

and encodes thyroid peroxidase, a key enzyme involved in this process. Mutations in these genes can re-

sult in thyroid dysfunction characterized by reduced levels of thyroid hormones. Hypothyroidism caused

by TPO pathogenic variants typically presents as permanent hypothyroidism and is frequently associated

with endemic goiter. This analytical review summarizes and systematizes data from the studies conducted

in different regions of the world on mutations identified in the TPO gene in patients with hypothyroidism.

Particular attention is given to mutations within structural and functional domains of thyroid peroxidase,

which has a unique molecular architecture within its family.

DOI: 10.1134/S0006297925604265

Keywords: thyroid autoantigens, thyroid peroxidase, hypothyroidism, TPO gene, mutations

* To whom correspondence should be addressed.

INTRODUCTION

Thyroid peroxidase (TPO) plays a key role in the

biosynthesis of thyroid hormones and is one of the

principal thyroid autoantigens. Autoantibodies against

TPO are detected in the serum of 90-100% patients

with autoimmune thyroid diseases (AITDs) [1-3]. One

of the underlying causes of autoimmune disorders

is a genetically determined defect in immunological

surveillance. Mutations in genes involved in thyroid

hormone biosynthesis, including the TPO gene, may

lead to thyroid dysfunction accompanied by thyroid

hormone deficiency [4]. Decreased thyroid function

manifests as clinical or subclinical hypothyroidism

and may develop in the context of both autoimmune

and non-autoimmune thyroiditis. Among thyroid pa-

thologies, hypothyroidism with autoimmune thyroid-

itis (AIT) accounts for 20.0-40.0% cases in adults and

~7.2% cases in children, depending on the iodine

endemicity in a given region [1,  2]. Congenital hypo-

thyroidism (CH), the clinical manifestations of which

most commonly include goiter and persistent hypo-

thyroidism (PH), occurs in ~1 in 2000-4000 newborns.

Thyroid dysgenesis is responsible for ~85% cases of

persistent primary goiter, while congenital defects in

the thyroid hormone biosynthesis (dyshormonogene-

sis) account for 10-15% of cases [5,  6]. Lowering the

thyroid-stimulating hormone (TSH) cut-offs in neo-

natal screening, together with demographic changes,

have led to an almost twofold increase in the re-

ported incidence of CH – from 1  :  3500 to 1  :  1714.

Additional cases identified at the lower TSH cut-offs

are generally associated with milder forms of hypo-

thyroidism [7].

TPO is located on the apical membrane of thy-

rocytes that faces the thyroid follicle lumen. The lu-

men contains colloid, which is composed primarily of

thyroglobulin, the largest and most important thyroid

autoantigen. TPO is a glycosylated hemoprotein that

catalyzes several essential steps in the synthesis of

the thyroid hormones thyroxine (T4) and triiodothy-

ronine (T3). Specifically, TPO oxidizes iodide in the

presence of hydrogen peroxide to generate molecu-

lar iodine, which subsequently iodinates tyrosine res-

idues in the thyroglobulin molecule [3, 8].

Mutations in the TPO gene can impair produc-

tion of thyroid hormones. Inactivating mutations un-

derlie a specific form of thyroid dysfunction, thyroid

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

dyshormonogenesis, occurring due to complete (total

iodide organification defect, TIOD) or partial (par-

tial iodide organification defect, PIOD) failure of io-

dide organification. TIOD represents the prevalent

phenotype among these autosomal recessive disor-

ders [9-11].

The first publication devoted to the study of

mutations in the TPO gene dates back to 1992. Abra-

mowicz et  al. [12] were the first to describe a TPO

gene mutation identified in a patient with CH. They

demonstrated that the patient was homozygous for

a frameshift mutation caused by a 4-bp insertion in

exon 8 of the TPO gene.

Over the following decade, numerous reports

have been published on the identification of TPO

mutations in the genomes of patients with thyroid

diseases, including findings from large population

studies, that have led to the publication of several

comprehensive review articles. In most cases, TPO

mutations have been discussed alongside alterations

in other genes involved in the thyroid hormone bio-

synthesis and embryonic thyroid development. For

example, a review by Troshina et  al. [4] analyzed

mutations in the TSHR (thyroid-stimulating hormone

receptor), NIS (sodium-iodide symporter/SLC5A5), TPO,

THOX (dual oxidase2/DUOX2), and TG (thyroglobulin)

genes and associated clinical phenotypes, focusing on

genetic disorders of thyroid hormone biosynthesis

(hormonogenesis) [4].

The prevalence of hypothyroidism caused by mu-

tations in the TPO gene varies considerably across

different regions of the world. Reported rates include

1  :  66,000 in the Netherlands [13]; 1  :  20,000 in Slo-

venia, Bosnia, and Slovakia [14]; 1  :  177,000 in Japan

[15, 16]; and 1  :  40,000 in Israel [17]. Newborn screen-

ing data from China indicate that the incidence of

TPO-related hypothyroidism in China is higher than

the global average. In Xinjiang, a region in the north-

west China accounting for approximately one-sixth of

the country’s territory, the incidence was reported as

1 in 1468 newborns. This rate is higher than that ob-

served in Guangxi (1%), located in southern China,

but lower than the rate reported in Shanghai (10%)

in eastern China [18,  19]. In Iran (Isfahan), a neona-

tal screening program for CH was initiated in 2002.

The frequency of TPO gene mutations in this popu-

lation was estimated at 1  :  357 newborns, which is

approximately ten times higher than the rates report-

ed in comparable studies from North America and

Europe [20].

Cases involving combinations of mutations in the

TPO gene and sensorineural hearing loss have been

reported [21]. Evidence suggests that hearing loss as-

sociated with TPO gene mutations is secondary and

results from the thyroid hormone deficiency during

critical early developmental stages (embryonic and

neonatal periods), leading to the delayed maturation

of inner ear structures [22].

TPO plays a crucial role not only in the thyroid

hormone synthesis and maintenance of normal thy-

roid function, but also in the diagnostics and treat-

ment of various thyroid disorders. Studies have

shown that TPO is highly expressed in normal thy-

roid tissue and in benign thyroid diseases, whereas

its expression in papillary thyroid carcinoma is weak

or absent, which is used to distinguish between be-

nign and malignant thyroid lesions clinically [23].

Certain TPO genetic variants have been reported as

associated with thyroid carcinoma and hypoechoic

thyroid nodules [23, 24].

TPO GENE STRUCTURE

The TPO gene was cloned in 1987 its full-length

mRNA transcript is 3048 bp long. The gene has an

exon–intron organization and is located on the short

arm of chromosome  2 (2p25.3) [25]. In addition to the

full-length TPO-1 isoform, which comprises 933 amino

acid (a.a.) residues and includes all exons, characteri-

zation of the exon–intron boundaries in the TPO gene

revealed at least ten alternatively spliced isoforms

that differ from the canonical form by the exclusion

of one or more exons. Analysis of TPO mRNA expres-

sion in normal thyroid tissue showed that only 19%

transcripts were the full-length mRNA, whereas the

remaining 81% were truncated mRNA variants. The

most prevalent transcript (56%) encodes the TPO-2

isoform, which lacks the residues 533-589 encoded by

exon  10. However, subsequent studies demonstrated

that this isoform is unable to bind heme, a property

essential for the TPO enzymatic activity [26, 27].

The TPO-1 protein includes three main structural

regions: an extracellular domain (residues 1-846), a

transmembrane domain (residues 847-871), and an in-

tracellular domain (residues 872-933). Analysis of the

TPO primary sequence reveals homology between one

of the regions and the complement control protein

(CCP) domain; another TPO region was homologous

to the epidermal growth factor (EGF)-like domain, a

feature commonly observed in membrane-bound en-

zymes. The binding of the heme prosthetic group is

mediated by two conserved histidine residues, distal

His239 and proximal His494. TPO contains five po-

tential N-glycosylation sites, four of which (Asn129,

Asn307, Asn342, and Asn569) are located in the ex-

tracellular domain [3, 8].

Comprehensive population analysis and bioinfor-

matic characterization of TPO variants cataloged in

the Genome Aggregation Database (gnomAD) v.2.1.1

were reported in a 2022 review [28], which identi-

fied 183 distinct TPO variants. The study analyzed

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

the distribution of cytosine substitution variants,

nonsense mutations, frameshifts, and splice (acceptor/

donor) site mutations across different ethnic groups.

Based on the gnomAD v2.1.1 dataset, the estimated

prevalence of heterozygous carriers of potentially del-

eterious TPO variants was 1 in 77.

Reports of TPO mutations in patients with func-

tional thyroid disorders continue to accumulate,

making the publication of a dedicated review on

the most frequently identified mutations in patients

with CH across different regions particularly timely.

In the present review, we described the distribution

of mutations across various TPO domains, including

those located near catalytically active sites and within

immunodominant regions (IDRs), i.e., TPO fragments

binding antibodies in the sera of patients with AITDs,

with special attention to the types of mutation and

its association with clinical manifestations of hypo-

thyroidism.

TPO GENE MUTATIONS

Mutations in the TPO extracellular domain.

The extracellular domain of TPO, located on the out-

er surface of the thyrocyte, was reconstructed using

computer modeling. This domain is characterized by

the presence of myeloperoxidase (MPO)-like region

(a.a.  142-733), which exhibits the enzymatic activity

and is highly homologous to the human MPO. It is fol-

lowed by the CCP-like region (a.a.  739-795), which en-

ables TPO to directly activate complement without the

involvement of immunoglobulins [29]. The last frag-

ment of the TPO extracellular domain is the epidermal

growth factor (EGF)-like region (a.a. 796-841) [30].

The extracellular domain is a hotspot for numer-

ous mutations in the TPO gene.

Mutations in the TPO gene sequence encoding res-

idues 1-141 of the extracellular domain. This fragment

contains the catalytically active sites and the first gly-

cosylation site of the extracellular domain (Asn129).

The data on TPO mutations identified in the genomes

of patients with hypothyroidism from various regions

worldwide are summarized in Table  1, where they

are organized according to their position within the

domain and the chronological order of their discov-

ery. Associated clinical complications, including goiter,

multinodular goiter (MNG), Pendred syndrome, and

others, are reported for each case.

Ten mutations in the TPO gene were identified in

21 individuals in a cohort of 83 Turkish and 21 Paki-

stani patients with CH. Among these, two novel mu-

tations, Ala5Thr and Tyr55X, were located within the

1-141  a.a. fragment of the extracellular domain [31].

Clinical features observed in patients carrying the

Ala5Thr mutation were consistent with a partial loss-

of-function effect [32]. The nonsense mutation Tyr55X

was detected in two affected siblings from a single

family, both of whom exhibited TIOD. Nonsense mu-

tations occurring in the N-terminal sequence-coding

region of the TPO gene are known to entirely abol-

ish the enzymatic activity of TPO, leading to severe

impairment of iodide organification and consequent

thyrotoxicosis [33].

A multicenter genomic study of 49 patients with

CH from the UK and Middle Eastern countries iden-

tified the frameshift mutation Glu17AspfsX77 located

in the 1-141  a.a. fragment of the extracellular domain

was identified in a patient with hypothyroidism com-

plicated by the Pendred syndrome [34].

Analysis of genomes of 230 Chinese patients

with CH identified 35 mutations in the TPO gene in

23 individuals (10.0%). Among these patients, biallel-

ic mutations were detected in 13 individuals, while

heterozygous mutations were found in 10 patients.

Anovel mutation (Ser37Pro) located at the extracellu-

lar domain N-terminus was identified in one patient

[35]. A frameshift mutation (a 20-bp duplication in

exon  2) was identified in a genomic study of a TIOD

patient from the Netherlands [36]. In a subsequent

publication, the same authors reported that among 16

TPO gene mutations identified in 45 Dutch patients

with TIOD, the frameshift mutation ins20bp141 was

detected in five individuals. This mutation introduces

a premature stop codon in exon  3 [13].

A molecular genetic study of 244 Russian patients

with CH identified 20 TPO variants representing dif-

ferent types of nucleotide changes (including 15 novel

variants) in 30 patients (12.3%). Compound heterozy-

gous mutations were detected in 9 patients, while het-

erozygous mutations were identified in 21 patients.

These TPO gene defects included frameshift-inducing

insertions and deletions (n  =  4), a nonsense mutation

(n  =  1), missense mutations (n  =  13), and intronic mu-

tations leading to aberrant splicing (n  =  2). Five mu-

tations were localized within the N-terminal extracel-

lular domain of TPO (residues 1-141). The Pro70Ala

mutation was identified in two patients; in one case,

it occurred as part of a compound heterozygous mu-

tation (Pro70Ala/Cys808AlafsX24, exon  14). The het-

erozygous nonsense mutation Arg89X was detected

in a patient with CH without goiter. The compound

heterozygous mutation Arg89X/Ala397ProfsX76, affect-

ing the 1-141  a.a. region of TPO, was identified in a

patient with hypothyroidism complicated by the Pen-

dred syndrome [17, 33], as well as in another patient

with hypothyroidism and MNG. Additionally, the com-

pound heterozygous mutation Met94Thr/Asp240Val

was detected in a patient with hypothyroidism com-

plicated by goiter. The heterozygous Ser97Pro muta-

tion was found in two patients with CH, including

one case complicated by goiter [37].

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Table 1. Mutations in the TPO gene fragment encoding residues 1-141 of the extracellular domain

Mutation and/or change

in the TPO protein sequence

resulting from TPO mutations

Region,

country

n Mutation type Clinical manifestation

of hypothyroidism

Reference

Ala5Thr Turkey 1 Hom TIOD [31]

Ala5Thr Turkey 1 Hom PIOD [32]

Glu17AspfsX77 UK (+) 1 ComHet Pendred syndrome [34]

Ser37Pro China 1 Het HP [35]

ins20 bp141 Netherlands 1 ComHet TIOD [36]

ins20 bp141 Netherlands 5 ComHet TIOD [13]

Tyr55X Turkey 2 Hom hypoplasia/

Tourette syndrome

[31]

Tyr55X Turkey 2 Hom TIOD [33]

Pro70Ala Russia 1 Het PH [37]

Pro70Ala Russia 1 ComHet PH [37]

Glu72fsX86 Argentina 1 ComHet TIOD [38]

Arg89X Turkey 1 Het goiter [39]

Arg89X Russia 1 ComHet Pendred syndrome [22]

Arg89X Russia 2 Het hypoplasia [37]

Arg89X Russia 2 Het goiter [37]

Arg89X Russia 1 ComHet MNG/Pendred syndrome [37]

Met94Thr Russia 1 ComHet goiter [37]

Ser97Pro Russia 1 Het goiter [37]

Ser97Pro Russia 1 Het PH [37]

Asn129fsX208 Argentina 2 Het TIOD/goiter [9]

Asn129fsX208 Argentina 1 ComHet TIOD [38]

Ser131Pro Portugal 1 ComHet goiter [40]

Ser131Pro Russia 1 ComHet MNG [37]

insGGCC395 Italy 1 Hom MNG/BRRS [41]

Pro135His China 1 Het PH [19]

Note. Mutations (or amino acid substitutions) identified repeatedly in different countries are shown in bold; mutations in

the TPO nucleotide sequence are shown in italic; n, the number of carriers of the identified mutation in the study; UK (+)

represents United Kingdom, Oman, Saudi Arabia, UAE, and Turkey; Het, heterozygous mutation; Hom, homozygous mutation;

ComHet, compound heterozygous mutation; BRRS, Bannayan–Riley–Ruvalcaba syndrome. For other abbreviations, see the

text of the article.

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

Rivolta et al. [38] described the compound hetero-

zygous mutation c.215delA/c.2422T>C (p.Glu72fsX86/

p.Cys808Arg) identified in the genome of an Argentin-

ian patient with hypothyroidism associated with the

iodide organification defect [38]. The heterozygous

mutation Arg89X was detected in  utero in an embryo

of a patient from Turkey with hypothyroidism com-

plicated by goiter. The nonsense mutation c.265C>T

located in exon  4, leads to the formation of a stop

codon at position 89 and, as a consequence, to a se-

vere truncation of the TPO protein with a complete

loss of its heme-binding site [39].

In a cohort of 40 Argentinian patients with hy-

pothyroidism and goiter, 14 individuals with an io-

dide organification defect were selected for genomic

analysis. Mutations in the TPO gene were identified

in seven of these patients. One patient was a com-

pound heterozygote carrying two TPO mutations,

whereas the remaining patients were heterozygous

for a single TPO mutation. Five novel mutations

were detected, including one single-nucleotide de-

letion and four single-nucleotide substitutions. The

c.387delC (p.Asn129fsX208) frameshift mutation was

identified in exon  5 [9]. The same mutation was lat-

er reported in the compound heterozygous genotype

Asn129fsX208/Gly387Arg [38]. Notably, this mutation

affects Asn129 residue, the first glycosylation site in

the TPO extracellular domain.

Among 55 patients with CH treated at clinics

in the Portugal’s capital, the novel missense muta-

tion c.391T>C (p.Ser131Pro) was identified in one

patient in a compound heterozygous state with

Cys808AlafsX23 [40]. The same p.Ser131Pro variant

was also reported as a compound heterozygous mu-

tation with g.IVS13+2T>G in a Russian patient with

hypothyroidism complicated by MNG [37]. The homo-

zygous insGGCC395 mutation was found in an Ital-

ian patient with CH and Bannayan–Riley–Ruvalcaba

syndrome (BRRS), who also developed MNG [41].

Finally, the heterozygous Pro135His mutation was

identified in the genome analysis of 219 patients with

hypothyroidism from northwestern China [19].

In conclusion, mutations affecting the TPO ex-

tracellular domain of (residues 1-141) are rare and

usually observed in isolated cases. Fourteen such

mutations have been identified, including three ho-

mozygous mutations, a missense mutation (Ala5Thr),

a nonsense mutation (Tyr55X), and a frameshift

mutation (insGGCC395), as well as eight compound

heterozygous mutations.

The Arg89X mutation was detected in patients

with CH from Russia and Turkey, whereas the

Ser131Pro mutation was found in patients with CHC

from Russia and Portugal. The Arg89X mutation was

detected in seven patients presenting with diverse

hypothyroidism phenotypes and associated com-

plications, including goiter, MNG, and Pendred syn-

drome.

Mutations in the MPO-like fragment (residues

142–733) of the TPO extracellular domain. The MPO-

like fragment of the TPO extracellular domain (resi-

dues 142-733) contains sequences primarily respon-

sible for the TPO enzymatic activity, three N-linked

glycosylation sites (Asn307, Asn342, and Asn569),

two histidine residues (distal His239 and proximal

His494) directly involved in coordination of the heme

prosthetic group essential for the TPO catalytic func-

tion [3,8], and an IDR that binds anti-TPO antibodies

in the serum of patients with AITDs. It was found

that the IDR comprises two overlapping regions,

designated as domains A and B. Domain  A (IDR/A;

residues 456-631) contains the main binding site for

IDR/A-specific monoclonal antibodies (mAbs) located

within residues 599-617. Domain  B (IDR/B) is com-

posed of five discrete regions: a.a.  210-225, 353-363,

549-563, 713-717, and 766-775. Notably, truncation of

TPO after residue 771 had virtually no impact on the

protein recognition by autoantibodies in all tested

patient serum samples [3, 42].

Various strategies have been employed to study-

ing the TPO structure, including the use of recombi-

nant TPO proteins and anti-TPO mAbs. Serum autoan-

tibodies from patients with AITD (n  =  10) were tested

against peptides corresponding to the TPO fragments

590-622 and 710-722, revealing two surface epitopes

[43]. These results were obtained by ELISA with Fab

fragments of human mAbs against IDR/A and IDR/B,

which were tested against both native TPO and re-

combinant proteins immobilized on a solid phase.

The recombinant proteins included point mutations

at specific amino acid positions, such Arg225, Glu604,

Asp620, Asp624, Lys627, Arg646, and Asp707 [44].

Using ten mAb variants from a panel of 36, five

groups of antigenic determinants were identified in

the TPO molecule, encompassing both linear and

conformational epitopes. Linear epitopes (residues

606-617 and 706-720) were recognized by mAb1 and

contributed to the formation of the conformational

epitope  3, consistent with the three-dimensional mod-

els of TPO showing that these fragments are spatial-

ly close despite being separated in the primary se-

quence [45].

The data on mutations in the MPO-like region

identified in the genomes of patients with hypothy-

roidism from different world regions are presented

in Table  2.

Of 16 mutations identified in the genomes of

45 Dutch patients with TIOD, three were in the

MPO-like region and corresponded to three alterna-

tive splicing variants: G3C  439  GG/gt3GC/gt (exon  4),

G3A  1858  AG/gt3AA/gt (exon  10), and G3A  11 AG/

gt3AG/at (intron  10). The most common mutations

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Table 2. Mutations in the MPO-like region (residues 142-733) of the extracellular domain of TPO

Mutation and/or change

in the TPO protein sequence

resulting from TPO mutations

Region,

country

n Mutation type Clinical manifestation

of hypothyroidism

Reference

G3C 439 GG/gt3GC/gt Netherlands 1 Het TIOD [13]

Ala148Tyr Russia 1 Het PH [37]

483-2A>G Sudan 1 ComHet goiter [46]

Arg175Gln Japan 2 ComHet goiter/PH [47]

Arg175X Bosnia 1 ComHet goiter/Gardner syndrome [14]

Arg189Gln China 1 Het PH [35]

Asp223del Russia 2 ComHet PH [37]

670_672del Malaysia 2 ComHet goiter/PH [48]

Asp224del China 1 Het goiter [49]

Asp224del Japan 1 ComHet goiter [50]

224_224del China 3 ComHet goiter [35]

Gln235X Germany 1 ComHet Pendred syndrome [21]

Asp240Val Russia 1 ComHet PH [37]

Ala257Ser Tunisia 9 Hom goiter/Gardner syndrome [51]

Ala257Ser Tunisia 2 Hom Gardner syndrome [51]

Ala257Ser Tunisia 2 Het goiter/Gardner syndrome [51]

859G>T Iran 1 Het PH [20]

Gln266X Argentina 1 ComHet PH [52]

Cys269Ser China 1 ComHet PH [35]

820-2 A>G Japan 1 ComHet Goiter [50]

820-1G>A China 1 ComHet PH [19]

Arg279Trp China 1 Het goiter/PH [19]

843delC China (Taiwan) 1 ComHet TIOD [53]

Arg291His UK (+) 1 ComHet goiter [35]

Ser292Phe Israel 4 ComHet TIOD/goiter [17]

Ser292Phe Tunisia 2 Hom TIOD/MNG [51]

Asn307Ser Israel 1 Het TIOD/goiter [17]

Asn307Thr Argentina 2 Het TIOD/goiter [9]

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Table 2 (cont.)

Mutation and/or change

in the TPO protein sequence

resulting from TPO mutations

Region,

country

n Mutation type Clinical manifestation

of hypothyroidism

Reference

Ser309Pro China 1 Het PH [19]

Glu319Arg Turkey 2 Het goiter [54]

Glu319Arg Turkey 5 ComHet goiter [31]

Glu319Arg Turkey 2 Hom goiter [31]

Ala326Thr Netherlands 1 Het TIOD [13]

Gly331Val UK (+) 1 ComHet goiter [35]

Asp333Asn Pakistan 3 Hom TIOD [31]

Glu337Lys China 1 Het PH [19]

Arg341Gln Japan 2 ComHet PH [15]

Gly348Arg Russia 1 ComHet PH [37]

Arg361Leu China 1 Het hypoplasia [19]

Pro368Leu Chile 2 ComHet goiter [55]

1207G>T Iran 1 Het PH [20]

Gly387Arg Argentina 1 ComHet TIOD [38]

Gly387Arg Japan 2 Hom goiter [50]

1182_1183ins

CGGC

Finland 3 Hom PH [56]

1182_1183ins

CGGC

Finland 1 ComHet PH [56]

Arg396fsX472 Netherlands 1 ComHet TIOD [36]

Arg396fsX472 Netherlands 2 ComHet TIOD [13]

Arg396fsX472 Argentina 1 Het TIOD/goiter [9]

Arg396fsX472 Argentina 1 ComHet TIOD/goiter [9]

Arg396fsX472 Argentina 4 ComHet PH [52]

Ala397ProfsX76 Argentina 1 Hom TIOD/goiter [12]

Ala 397ProfsX76 Portugal 2 ComHet goiter [40]

Ala397ProfsX76 Portugal 2 Hom goiter [40]

Ala397ProfsX76 Bosnia 1 Het goiter/Gardner syndrome [14]

Ala397ProfsX76 Slovenia 4 Het goiter/Gardner syndrome [14]

THYROID PEROXIDASE GENE MUTATIONS S401

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Table 2 (cont.)

Mutation and/or change

in the TPO protein sequence

resulting from TPO mutations

Region,

country

n Mutation type Clinical manifestation

of hypothyroidism

Reference

Ala397Prof sX76 Slovenia 2 Het Gardner syndrome [14]

Ala397ProfsX76 Slovakia 1 Het follicular adenoma [14]

Ala397ProfsX76 Bosnia 3 ComHet goiter [14]

Ala397ProfsX76 Slovenia 3 Hom goiter/Gardner syndrome [14]

1184_1187 dup.GCCG Turkey 1 Hom Goiter [31]

Ala397ProfsX76 UK (+) 1 Het TIOD/Goiter [34]

Ala397Pro fsX76 Russia 1 ComHet Pendred syndrome [22]

Ala397ProfsX76 Russia 1 Het goiter [37]

Ala397ProsX76 Russia 2 ComHet MNG [37]

Ala397ProfsX76 Russia 1 Het hypoplasia [37]

1283G>C Iraq 1 Het PH [20]

1242G>T Brazil 2 ComHet PIOD/goiter [10]

Asn425Ser Portugal 1 ComHet goiter [40]

insGGCC1277 Netherlands 3 ComHet TIOD [36]

insGGCC1277 Netherlands 6 Hom TIOD [36]

insGGCC1277 Netherlands 13 ComHet TIOD [13]

insGGCC1277 Netherlands 12 Hom TIOD [13]

insGGCC1277 Brazil 4 Hom TIOD/goiter [10]

insGGCC1277 Brazil 2 ComHet TIOD/goiter [10]

Ala426Gly Sudan 3 Hom goiter [46]

Ala426Gly Sudan 1 ComHet goiter [46]

Trp428Arg China 1 ComHet PH [35]

Ala430Glu China 1 ComHet goiter [35]

Val433Met Argentina 1 ComHet TIOD/goiter [9]

His438Arg Finland 1 ComHet PH [56]

Ala443Val China 1 ComHet PH [19]

Ala443Pro China 2 Hom goiter [35]

Ala443Pro China 1 ComHet goiter [35]

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Table 2 (cont.)

Mutation and/or change

in the TPO protein sequence

resulting from TPO mutations

Region,

country

n Mutation type Clinical manifestation

of hypothyroidism

Reference

Ile447Phe Netherlands 1 Het TIOD [13]

Tyr453Asp Netherlands 1 ComHet TIOD [36]

Tyr453Asp Netherlands 9 ComHet TIOD [13]

Tyr453Asp Germany 1 ComHet goiter/Pendred syndrome [21]

Tyr453Asp UK (+) 1 ComHet Goiter [34]

1425delC Netherlands 1 Het TIOD [13]

Ala477Asn483del Slovenia 2 Het goiter/Gardner syndrome [14]

Ala477Asn483del Bosnia 2 Het goiter/Gardner syndrome [14]

Asn483Lys Russia 1 Het PH [37]

Ala489Thr Russia 2 ComHet PH [37]

Ala489Thr China 1 ComHet PH [35]

Arg491His UK (+) 1 ComHet TIOD/goiter [34]

Arg491His UK (+) 1 Hom TIOD/goiter [34]

Gly493Ser China (Taiwan) 1 ComHet TIOD [53]

Gly493Ser Portugal 2 Hom goiter [40]

Gly493Ser Israel 9 ComHet TIOD/goiter [17]

Gly493Ser Iraq 1 ComHet goiter [57]

Pro499Lys Argentina 1 Het TIOD/goiter [9]

1502T>G Malaysia 2 Hom MNG [58]

Glu510Ala UK (+) 1 Het PH [34]

Pro512His Sudan 2 ComHet goiter [46]

Trp527Cys Netherlands 1 Het TIOD [13]

Trp527Cys Japan 1 Hom TIOD/goiter [50]

Trp527Cys Russia 1 Het goiter [37]

1597+1G>T Brazil 1 Het PIOD/goiter [10]

Arg540X Netherlands 2 ComHet TIOD [36]

Arg540X Netherlands 4 ComHet TIOD [13]

Arg540X Israel 9 ComHet TIOD/goiter [17]

THYROID PEROXIDASE GENE MUTATIONS S403

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

Table 2 (cont.)

Mutation and/or change

in the TPO protein sequence

resulting from TPO mutations

Region,

country

n Mutation type Clinical manifestation

of hypothyroidism

Reference

Arg540X Turkey 3 Het goiter [54]

Arg540X Japan 2 ComHet PH [15]

Arg540X Iraq 2 ComHet goiter [57]

Arg540X Turkey 8 ComHet TIOD [31]

Arg540X Turkey 2 Hom TIOD [59]

Gly553Cys Japan 3 ComHet goiter [50]

Thr561Met China 1 ComHet goiter [18]

Ser571Arg China 1 Het goiter [19]

Asp574 Lys575 del Japan 3 ComHet goiter [50]

Ala576Val Germany 1 ComHet MNG [60]

Arg584Gln UK (+) 2 Hom PH [34]

Arg584Gln Russia 1 Het PH [37]

Gly587Arg Sudan 2 ComHet goiter [46]

Asn592Ser China 1 ComHet PH [19]

1780C>A Brazil 2 Het PIOD/goiter [10]

1780C>A Brazil 2 ComHet PIOD/goiter [10]

Arg595Lys Argentina 4 ComHet PH [52]

Arg595Lys Argentina 2 Hom PH [52]

Glu596X Pakistan 3 Hom TIOD [31]

Ser617Arg fsX23 Russia 1 Het PH [37]

Ser617Arg fsX23 Russia 1 ComHet PH [37]

G3A 1858 AG/gt3AA/gt Netherlands 3 Het TIOD [13]

G3A 11 intron 10 AG/gt3AG/atT/ Netherlands 1 Het TIOD [36]

G3A 11 intron 10 AG/gt3AG/atT/ Netherlands 1 Het TIOD [13]

1978 C>G Iraq 2 Het goiter [57]

Asp633Val Russia 1 Het PH [37]

Asp633Asn Pakistan 3 Hom TIOD [31]

Arg648Gln USA 3 ComHet TIOD [61]

ZUBKOV, BUTOVAS404

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

Table 2 (cont.)

Mutation and/or change

in the TPO protein sequence

resulting from TPO mutations

Region,

country

n Mutation type Clinical manifestation

of hypothyroidism

Reference

Arg648Gln China 1 ComHet goiter [13]

Ile657Thr China 1 ComHet goiter [49]

Ile657Thr China 1 Het PH [49]

Gln660Glu Brazil 1 ComHet TIOD/goiter [10]

Gln660 Glu Portugal 5 ComHet goiter [40]

Gln660 Glu Portugal 1 Hom goiter [40]

Arg665Thr Japan 1 ComHet TIOD/goiter [62]

Arg665Thr Japan 2 ComHet TIOD/goiter [47]

Arg665 Gln Argentina 1 Het TIOD/goiter [9]

Arg665 Gln Pakistan 4 ComHet TIOD [31]

Arg665 Gln Russia 1 Het PH [37]

2088C>T Iran 1 Het PH [20]

Gly667Asp Argentina 1 ComHet PH [52]

Gly667Ser Slovenia 1 Het MNG [14]

Glu673Lys Russia 4 Het PH [37]

Glu673Lys China 1 Het PH [19]

Asn674Ser China 1 Het goiter [19]

2068G>C Brazil 2 ComHet TIOD/goiter [10]

Arg693Trp Netherlands 2 Het TIOD [13]

2084G>A Brazil 2 Het PIOD/goiter [10]

2090G>A China 2 ComHet MNG [24]

Phe718X Netherlands 1 Het TIOD [13]

Note. For designations, see Note to Table 1.

were insGGCC1277, Tyr453Asp, Arg540X, and

Arg396fsX472 [13]. Previously, Dutch researchers

[36] reported seven different mutations among 15

patients from nine apparently unrelated families.

These included three frameshift mutations and four

single nucleotide substitutions. Among the patients,

nine individuals from five families were compound

heterozygotes, while six patients from four families

were homozygous for the insGGCC1277 mutation [36].

In a cohort of 43 patients with the Gardner syn-

drome and PH, representing 39 unrelated families

from Slovenia (30 patients), Bosnia (11 patients),

and Slovakia (2 patients), mutations in the TPO gene

were detected in 46% of participants. Seven different

mutations were identified, four of which (Arg175X,

Ala397ProfsX76, Ala477Asn483del, Gly667Ser) were

THYROID PEROXIDASE GENE MUTATIONS S405

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

located in the MPO-like region [14]. In a consanguin-

eous Israeli population with CH and persistent prima-

ry hypothyroidism, one novel mutation (Ser292Phe)

and two previously reported mutations (Gly493Ser

and Arg540X) were associated with idiopathic organi-

fication defects (IODs). The latter two mutations were

present in 90% of patients. Thyroid enlargement,

mostly multinodular and sometimes retrosternal, was

observed in 64% of patients, while neurological com-

plications occurred in 59% (13 patients). Four subjects

carrying two different TPO mutations exhibited senso-

rineural hearing loss, highlighting the need for long-

term follow-up in patients with TPO mutations [17].

A 12-year clinical study of 13 patients (10 men and 3

women) with thyroid dyshormonogenesis and Gard-

ner syndrome from three related Tunisian families

revealed significant phenotypic variability, includ-

ing goiter (9 patients), sensorineural hearing loss (4

patients), and mental retardation (6 patients). The

Ala257Ser mutation in a homozygous state was de-

tected in 11 subjects. Additionally, the previously

described Ser292Phe mutation was detected in ho-

mozygosity in two patients, both presenting with

multinodular thyroid enlargement. Missense muta-

tions are the most annotated changes in the TPO

gene; however, due to limited functional data, their

interpretation often involves in  silico analysis. Thus,

according to in  silico analysis, the Ser292Phe muta-

tion may reduce the TPO catalytic cavity, thereby

limiting substrate access to the enzyme’s active site

[51]. In a study of 219 patients with hypothyroidism

from northwestern China, the use of high-through-

put sequencing and bioinformatic analysis allowed to

identify 19 rare TPO variants in 17 individuals (7.8%),

including 7 novel variants. Most were heterozygous,

with two compound heterozygotes (g.IVS7-1G>A/

Ala443Val and Asn592Ser/Asn798Lys). The splicing

variant c.820-1G>A (g.IVS7-1G>A) in intron 7 may im-

pair mRNA splicing, producing an inactive protein

[19]. The study of 26 Sudanese families with CH and

goiter and suspected Gardner syndrome revealed

rare mutations in the MPO-like region, including

c.483-2A>G (g.IVS5-2A>G), Ala426Gly, Pro512His, and

Gly587Arg. The Ala426Gly mutation was observed in

three patients in a homozygous state and in one com-

pound heterozygote (Ala426Gly/Cys808AlafsX24) [46].

Two siblings with goitrogenic CH from Japan carried

two missense mutations, including novel c.614G>A

(p.Arg175Gln) mutation. In cotransfection experi-

ments in CHO-K1 cells, mRNA transcribed from the

mutant c.614G>A gene encoded TPO with a molecular

weight similar to that of the wild-type protein [47].

As mentioned above, mutations affecting the first ex-

tracellular glycosylation site (Asn129) were reported

in Argentina, along with mutations in the MPO-like

region. The c.920A>C (Asn307Thr) mutation affecting

the second glycosylation site, was detected in two

patients. Additionally, a GGCC duplication in exon  8

(c.1186_1187insGGCC, p.Arg396fsX472) was reported,

with one patient being a compound heterozygote

(Arg396fsX472/Val433Met)  [9]. The Glu319Arg muta-

tion has also been intermittently reported in Turkish

patients [31, 54]. In a combined cohort of 83 Turkish

and 21 Pakistani patients with PH and dyshormono-

genesis, seven TPO mutations were identified, includ-

ing two novel mutations (Glu596X, Asp633Asn) and

five previously described ones, all located in the 142-

733 fragment of the extracellular domain [31].

Screening by next-generation sequencing (NGS)

identified 49 cases of CH across 34 ethnically di-

verse families from the United Kingdom and the

Middle East. Putative CH-associated mutations were

found in 29 cases. Monogenic defects, four of which

were associated with TPO, were identified in 19 cas-

es. In ten cases, mutations were observed in differ-

ent genes, including six mutations in the TPO gene.

These included two known pathogenic missense mu-

tations (Arg491His, Arg665Gln), two novel frameshift

mutations (Cys808AlafsX24; Ala397ProfsX76), and two

novel missense mutations (Arg291His, Gly331Val)  [34].

Sequencing of the TPO gene in a German patient

revealed heterozygous mutations that resulted in a

stop codon at position 235 (novel nonsense mutation

Gln235X) and an amino acid substitution at codon

453 (known missense mutation Tyr453Asp) [21]. In a

cohort of 102 patients with CH from Japan, autoso-

mal recessive hypothyroidism was diagnosed in 14

individuals. Biallelic mutations in the TPO gene were

detected in the genomes of two patients: one muta-

tion led to the amino acid substitution at position 341

(novel missense mutation Arg341Gln) and the other

(c.1618C>T) resulted in a stop codon at position 540

(known nonsense mutation Arg540X) [15].

The genomes of twelve biologically unrelated

Malaysian-Chinese patients with CH were analyzed

for mutations in the TPO gene. Two novel mutations,

c.670_672del and c.1186C>T, were identified in four of

the twelve patients. In  silico analysis indicated that

these mutations are likely to disrupt the structure

and/or function of the TPO protein [48].

Analysis of the TPO gene in thirty Chinese chil-

dren with CH revealed six genetic variants in six

patients, including two inactivating heterozygous

mutations located in the 142-733 fragment of the

extracellular domain: c.670_672del (p.Asp224del)

and c.1970T>C (p.Ile657Thr) [49]. NGS-based genet-

ic screening showed that one Japanese patient was

a compound heterozygote for two TPO mutations

(p.Asp224del/g.IVS7-2 A>G), while another patient

was homozygous for the known Trp527Cys mutation.

In  vitro functional assays in HEK293 cells demon-

strated that both mutations led to a partial loss of

ZUBKOV, BUTOVAS406

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

enzymatic activity. These findings suggest a previously

unrecognized correlation between clinical phenotypes

and residual TPO enzymatic activity in patients with

the TPO deficiency. Additionally, three patients from

three different families were found to be compound

heterozygous for two TPO mutations (Gly553Cys/

Asp574Lys575del), while two other patients were ho-

mozygous for the known Gly387Arg mutation [50].

Three novel mutations, Gln266X, Arg595Lys, and

Gly667Asp, and a previously described mutation,

c.1186_1187insGGCC (p.Arg396fsX472), were identi-

fied in seven patients from four unrelated Argentine

families with CH. Four patients were compound het-

erozygotes for the Arg396fsX472/Arg595Lys mutations,

two patients were homozygotes for Arg595Lys, and

one patient had the compound heterozygous Gln266X/

Gly667Asp mutation [52]. Single-strand conformation

polymorphism (SSCP) method was used to detect TPO

mutations in five unrelated patients with TIOD in

Taiwan. Five novel mutations were detected; three of

them were frameshift mutations and two were single

deletions. The other two substitutions were single nu-

cleotide substitutions. A deletion of C at position 843

(c.843 del.C) in exon8 and a single nucleotide substi-

tution c.1477G>A, which results in the Gly493Ser sub-

stitution, are located in the MPO-like region of TPO

[53]. In Brazil, genome analysis of 14 patients with

goiter, including seven individuals with TIOD and

seven with PIOD, identified various TPO mutations.

Among TIOD patients from three families, a homozy-

gous GGCC insertion in exon 8 at position 1277 was

observed in family  1; a compound heterozygous GGCC

insertion in exon 8 at position 1277 together with the

c.2068G>C mutation in exon 11 was observed in fam-

ily  2; and a compound heterozygous c.2068G>C mu-

tation in exon  11 with a C nucleotide insertion of in

exon  14 between positions 2505 and 2511 was found

in family  3. In PIOD patients, heterozygous mutations

were detected in exon  10 (c.1780C>A) and exon 11

(c.2084G>A) in patients from families  4 and5, respec-

tively, while a compound heterozygous variant with

mutations in exons  8 and  10 (1242G>T and 1780C>A)

was identified in a patient from family  6. A hetero-

zygous mutation at the first nucleotide of the exon/

intron boundary (c.1597+1G>T, g.IVS9+1G>T) was de-

tected in a patient from family  8 [10].

Two different mutations were detected in five

children with congenital goiter from three consan-

guineous families from Turkey. A nonsense mutation

in exon  10 (Arg540X) was identified in affected chil-

dren from families  I and II, and a novel missense

mutation in exon  8 (Glu319Arg) was identified in

the third family  [54]. In a cohort from Chile, two

potentially pathogenic TPO mutations resulting in

Pro368Leu and Val748Met substitutions were identi-

fied in 2 of 12 patients (16.6%). One patient carried

compound heterozygous mutations c.1103C>T and

c.2242G>A, while the other patient was heterozygous

for c.2242G>A. Both patients presented with diffuse

goiter [55]. NGS performed in 15 patients with spo-

radic disease and 11 patients with familial disease

from Finland revealed Asp394fs and His438Arg mu-

tations in four patients with the familial disease [56].

The screening of 63 Arab patients from Iraq

(16 men and 47 women) with toxic and nontoxic

thyroid goiter revealed a total of ten heterozygous

mutations, including C→T substitution at position

1708 in exon  10 (c.1708C>T) and C→G substitution at

position 1978 in exon  11 (c.1978C>G). Among the ten

mutations detected, the c.1978C>G mutation was ob-

served in two patients with nontoxic goiter, whereas

the c.1708C>T and c.1978C>G mutations were found in

2 and 6 patients with toxic goiter, respectively. Over-

all, mutations in the TPO gene were predominantly

observed in women (90%) and in adults aged 30-50

years (80%) [57].

The screening for TPO mutations in two siblings

with CH and MNG and in healthy members of their

Malaysian families demonstrated that both sisters

were homozygous for the novel mutation c.1502T>G.

This variant is predicted to result in the replacement

of highly conserved Val501 residue with glycine

(p.Val501Gly). In  silico analysis using the PolyPhen-2

and SIFT programs showed that the Val501Gly sub-

stitution is functionally damaging to the protein. Fur-

thermore, tertiary structure modeling demonstrated

alterations in the TPO active site  [58]. The homozy-

gous nonsense mutation c.1618C>T (p.Arg540X), was

identified in the TPO genes of two Turkish patients

with TIOD. All unaffected family members were ei-

ther heterozygous carriers or homozygous for the

wild-type allele, supporting the pathogenic role of

this mutation [59].

The Arg665Trp mutation was identified in a com-

pound heterozygous state together with Arg175Gln

(Arg175Gln/Arg665Trp) in two Japanese patients [47].

In a separate study, direct sequencing of all exons

and flanking regions of the TPO gene was performed

in a 26-year-old German man of Thai origin with

CH complicated by MNG and in his family members.

This analysis revealed compound heterozygosity for

two TPO mutations: the novel missense mutation

c.1727C>T in exon  10, resulting in the Ala576Val sub-

stitution, and the c.2268_2269insT insertion in exon

13, causing a frameshift and introduction of a prema-

ture stop codon at position 757 (Glu757X) [60].

NGS analysis of the TPO gene in 192 Chinese pa-

tients with CH identified three distinct mutation vari-

ants in two individuals. Further sequencing of other

hemochromatosis-associated candidate genes revealed

that patient  1 was homozygous for the c.2422delT mu-

tation and also carried two heterozygous pathogenic

THYROID PEROXIDASE GENE MUTATIONS S407

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

variants in DUOX2. Patient 2 harbored pathogenic

TPO variants Arg648Gln and Thr561Met. This study

identified one novel mutation (Thr561Met) and two

previously reported mutations (Cys808AlafsX24 and

Arg648Gln), demonstrating a 1% prevalence of TPO

mutations among the examined Chinese CH cohort

[18]. In a separate study from Portugal, eight dif-

ferent TPO mutations, including three novel mis-

sense variants, were identified in 13 patients (sev-

en homozygotes and six compound heterozygotes)

selected from a cohort of 723 individuals with CH.

Notably, four mutations (Ala397ProfsX76, Asn425Ser,

Gly493Ser, and Gln660Glu) were located within the

MPO-like fragment [40].

TPO gene mutations in the genomes of CH pa-

tients with dyshormonogenesis from Isfahan were

less frequent compared to other studies. Using the

SSCP method and sequencing, six known single nu-

cleotide polymorphisms (SNPs) were detected in a

cohort of 41 patients. Two SNPs (G11A, A35G) were

located in the promoter region and exon 1; the other

four were in the sequence encoding the MPO-like re-

gion: c.859G>T, c.1207G>T, c.1283G>C, and c.2088C>T

(Table  2) [20]. In a study of 15 members of a Chinese

family, the compound heterozygous mutation c.2268-

2269insT*/c.2090G>A was detected in the genomes

of two patients with congenital goiter [24]. The TPO

genes of the patient with CH from Japan and her par-

ents were sequenced directly, and two missense mu-

tations, Arg665Trp and Gly771Arg, were detected. The

first mutation was inherited from the patient’s father,

and the second mutation from her mother [62].

In conclusion, mutations in TPO gene sequence

encoding the MPO-like region (a.a.  142-733) of the ex-

tracellular domain are rare and occur sporadically.

Among the 95 mutations identified in this region, 20

were observed in a homozygous state, while 56 oc-

curred as compound heterozygous variants.

Homozygous mutations are Ala257Ser, Ser292Phe

(Tunisia); Glu319Arg, Ala397ProfsX76, Arg540X (Tur-

key); Asp333Asn, Glu596X, Asp633Asn (Pakistan);

c.1182_1183insCGGC (Finland); Gly387Arg, Trp527Cys

(Japan); Ala397ProfsX76, Gly493Ser, Gln660Glu (Por-

tugal); Ala397ProfsX76, Arg595Lys (Argentina);

insGGCC1277 (Netherlands); insGGCC1277 (Brazil);

Ala426Gly (Sudan); Ala443Pro (China); Arg491His,

Ala584Gln (UK+); Val501Gly (Malaysia).

Each country exhibits its own spectrum of mu-

tations identified in patients with CH. Several iden-

tical mutations have been reported in CH patients

from different regions of the world. These include

Ser292Phe (Tunisia, Israel); Arg396fsX472 (Argentina,

Netherlands); Ala397ProfsX76 (Argentina, Portugal,

Russia, Slovenia, UK+); insGGCC1277 (Brazil, Neth-

erlands); Tyr453Asp (Netherlands, Germany, UK+);

Ala489Thr (Russia, China); Gly493Ser (Portugal, Tai-

wan, Israel, Iraq); Trp527Cys (Russia, Netherlands,

Japan); Arg540X (Netherlands, Israel, Iraq, Turkey,

Japan); Arg584Gln (UK+, Russia); Arg648Gln (USA,

China); Arg665Gln (Argentina, Russia, Pakistan);

Gly673Lys (Russia, China).

A total of 29 mutations have been identified

in the TPO fragment corresponding to IDR/A (resi-

dues 456-631). Five of these mutations (Ala489Thr,

Gly493Ser, Trp527Cys, Arg540X, and Arg584Gln) were

detected repeatedly.

Three mutations were identified in the TPO se-

quence encoding the MPO-like fragment correspond-

ing to IDR/B (residues 210-225, 353-363, 377-386, 549-

563, and 713-717). Among them, the c.670_672del

(p.Asp224del) mutation were detected repeatedly.

No recurrent mutations have been reported in

the TPO fragments 561-575, 590-622, and 710-722,

i.e., regions representing the greatest interest to im-

munologists. Three mutations were identified in the

561-575 region, including the compound heterozy-

gous variant Asp574_Lys575del. The 590-622 region

harbored five mutations, in particular, the homozy-

gous variants Arg595Lys and Glu596X. The 710-722

region contained only a single heterozygous mutation

(Phe718X).

It is necessary to highlight two mutations in the

MPO-like region: Ala397ProfsX76 and Arg540X, both

of which are located outside of IDRs.

The frameshift mutation c.1184_1187insGCCG is a

4-bp insertion in exon 8, resulting in p.Ala397 ProfsX76.

This mutation has been detected in 26 patients with

CH from eight countries across two continents. Among

these cases, 22 presented with the goitrous form of

CH. Seven patients were homozygous, and another

seven patients were compound heterozygous. The

c.1184_1187insGCCG (p.Ala397ProfsX76) mutation was

first reported in 1992 in a patient from Argentina

[12] and has since been repeatedly identified in CH

patients from multiple European and Asian countries

[14, 22, 31, 34, 37, 40].

The nonsense mutation c.1618C>T in exon 10,

resulting in a premature stop codon at position 540

(p.Arg540X), was identified in 30 patients with CH

from six Eurasian countries. The variant was homo-

zygous in 2  patients and compound heterozygous in

25  patients. Goiter was observed in 14 patients. The

Arg540X mutation was first reported in a Dutch pa-

tient in 1995 [36] and has since been repeatedly de-

tected in CH patients from multiple European and

Asian populations [13, 15, 17, 31, 54, 57, 59].

Mutations in the TPO gene sequence encoding the

CCP-like region (residues 739-795) of the extracellular

domain. The data on mutations in the TPO region

739-795 are summarized in Table  3.

The IDR/B includes the antigenic determinant

766-775.

ZUBKOV, BUTOVAS408

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

Table  3. Mutations in the TPO sequence encoding the CCP-like region (residues 739-795) in the TPO extracellular

domain

Mutation and/or change

in the TPO protein sequence

resulting from TPO mutations

Region,

country

n Mutation type Clinical manifestation

of hypothyroidism

Reference

del TT 2243/2244 Netherlands 1 ComHet TIOD [13]

Val748 Met China 1 Het PH [34]

Val748Met Chile 1 Het goiter [55]

Val748Met Chile 1 ComHet goiter [55]

2266T>C Malaysia 1 ComHet goiter/PH [48]

Cys756Arg China 1 ComHet goiter [49]

Cys756 Arg Germany 2 ComHet goiter [63]

Cys756fsX China 4 ComHet goiter [35]

Cys756fsX China 3 Hom goiter [35]

Cys756fsX China 1 Het goiter [35]

2268dup. Malaysia 2 Hom MNG [65]

2268dup. Malaysia 4 ComHet goiter/PH [48]

Glu757X China 2 Hom goiter [49]

Glu757X China 2 ComHet goiter [49]

Glu757X China 1 Het PH [19]

2268-2269 insT* China (Taiwan) 4 ComHet TIOD [53]

2268-2269 insT* China 4 Het MNG [24]

2268-2269 insT* China 2 ComHet goiter [24]

2268-2269 insT* China 1 Het papillary cancer [24]

2268-2269 insT* Germany 1 ComHet MNG/PH [60]

Leu764Pro China 1 Hom PH [35]

Arg769Trp China 1 ComHet PH/LBV [19]

Gly771Arg Japan 1 ComHet TIOD [62]

Gly771Arg Pakistan 4 ComHet TIOD [31]

Note. For designations, see Note to Table1; LBV, likely benign variant.

Out of 16 mutations identified in a study of ge-

nomes from 45 Dutch patients with TIOD, only the

c.del.TT2243/2244 deletion was located in the extra-

cellular domain region 739-795 [13].

Among the 35 mutations identified across 23

of 230 Chinese patients with CH, Table  3 highlights

three specific mutations: one heterozygous variant,

Val748Met, and two homozygous variants, Cys756fsX

THYROID PEROXIDASE GENE MUTATIONS S409

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

and Leu764Pro [35]. Notably, the Val748Met mutation

was also observed in 2 of 12 CH patients from

Chile [55].

Two Malaysian sisters with goiter were found

to carry the homozygous c.2268dup mutation, which

generates both normal and alternatively spliced

mRNA transcripts, ultimately leading to the loss of

the TPO enzymatic activity. The c.2268dup mutation

is predicted to introduce a premature stop codon at

position 757 (p.Glu757X). Rather than restoring the

normal reading frame, the alternatively spliced tran-

script contains a different premature stop codon at

position  740 (p.Asp739ValfsX740). In the initial phase

of this study, a shorter native form of TPO was de-

tected in both patients using the MoAb47 antibody,

which recognized an epitope within the 713-721  a.a.

region [65].

Genomic analysis revealed the c.2268dup mu-

tation in 4 out of 12 unrelated Malaysian-Chinese

patients with CH. Notably, one patient also har-

bored a second mutation, c.2266T>C, in addition to

c.2268dup [48].

Six mutations were identified by molecular analy-

sis in six patients with goiter in a study of thirty Chi-

nese children with CH. Two of these mutations, corre-

sponding to the Cys756Arg and Glu757X substitutions,

had been previously reported and were in the 739-

795  a.a. fragment of the extracellular domain. The

Glu757X mutation was found in four patients: as a

homozygous variant in the twins and as a compound

heterozygous variant in two unrelated patients [49].

Compound heterozygous mutations were iden-

tified in two children with CH from Germany. Both

children harbored an identical novel mutation in

exon  13 (Cys756Arg). One of the children exhibited

dominant inheritance of thyroid dyshormonogenesis

[60]. As previously mentioned, five novel TPO muta-

tions were detected in five unrelated patients with

TIOD from China (Taiwan). Among these, the frame-

shift mutation c.2268-2269insT* (a single insertion of

T between nucleotides 2268 and 2269) in exon  13 is

presented in Table  3. Of all the TPO mutations iden-

tified, c.2268-2269insT* was the most common, occur-

ring in a heterozygous state in all TIOD patients ex-

cept one. All five patients with TIOD were compound

heterozygotes [53]. Further investigation revealed the

c.2268-2269insT* mutation in four individuals from a

Chinese family of 15 members with normal thyroid

hormone levels; heterozygotes displayed degenerative

hypoechoic thyroid nodules. Compound heterozygous

mutations c.2268-2269insT*/c.2090G>A were identified

in two patients with congenital goiter. Additionally,

the c.2268-2269insT* mutation was detected in a pa-

tient with a multifocal papillary thyroid carcinoma

with lymph gland and nerve invasion in the left lobe

of thyroid gland. [24]. Genomic analysis revealed the

compound heterozygous mutation c.2268_2269insT*/

c.1727C>T in a German patient of Thai origin with CH

complicated by MN, which was inherited from both

parents as a novel mutation in exon  10 from his Ger-

man mother and mutation in exon  13 from his Thai

father. Bioinformatic analyses using two programs

predicted that this variant likely disrupts the struc-

ture of the TPO protein [63].

The study analyzing genomes of 219 Chinese

patients with hypothyroidism revealed the hetero-

zygous variant Glu757X and the compound hetero-

zygous variant Arg769Trp in the TPO fragment 739-

795  a.a. [19]. The compound heterozygous mutation

Arg665Trp/Gly771Arg was identified in a Japanese

patient with CH, where the Arg665Trp was inherited

from the father and Gly771Arg was inherited from

the mother [66].

A study of 21 patients from Pakistan with CH com-

plicated by the tetra-amelia syndrome identified ten

mutations, one of them being Gly771Arg (Table  3)[31].

In conclusion, among the 11 identified mutations,

two were homozygous (Cys756fsX and Leu764Pro,

both reported in China) and the remaining nine were

compound heterozygous. Additionally, four identical

mutations were observed in patients with CH from

different regions worldwide: Val748Met (Chile, China),

Cys756Arg (Germany, China), p.2268-2269insT* (Ger-

many, China), and Gly771Arg (Japan, Pakistan).

The c.2268-2269insT* mutation was identified in

12 patients with diverse hypothyroidism phenotypes

and various complications (goiter, MNG, cancer, etc.).

Therefore, in certain cases, TPO genetic variants

may be associated with thyroid carcinoma and hy-

poechoic thyroid nodules. Two mutations were iden-

tified in the TPO nucleotide sequence, affecting the

766-775  a.a. fragment of IDR/B, including recurrently

observed Gly771Arg mutation.

Mutations in the TPO nucleotide sequence en-

coding the EGF-like region (residues 796-841) of the

extracellular domain. The data on mutations in the

TPO region 796-841  a.a. are presented in Table  4. This

region is not classified as an IDR.

Five compound heterozygous mutations were

identified in five unrelated patients with TIOD from

Taiwan. Among these, a single nucleotide substitu-

tion, c.2386  G>T, either results in an amino acid sub-

stitution (Asp796Tyr) or affects splicing, while a sin-

gle nucleotide deletion, c.2413delC, is located within

the region encoding the EGF-like domain (residues

796-841) [53]. In addition, mutations in intron  13,

including c.2386+2  T>G (g.IVS13+2  T>G), have been

reported in a patient with MNG from Russia [37].

The rare Asn798Lys mutation was identified in a pa-

tient with congenital goiter from a 15-member family

in China [19]. Furthermore, Glu799Lys and the inser-

tion mutation insC2505-2511 were detected as part of

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

Table 4. Mutations in the TPO gene sequence coding for the EGF-like region (residues 796-841) of the extra-

cellular domain

Mutation and/or change

in the TPO protein sequence

resulting from TPO mutations

Region,

country

n Mutation type Clinical manifestation

of hypothyroidism

Reference

2386G>T China (Taiwan) 2 ComHet TIOD [53]

2386+2T>G Russia 1 ComHet MNG [37]

Asn798Lys China 1 ComHet goiter [21]

Glu799Lys Netherlands 1 ComHet TIOD [36]

Glu799Lys USA 3 ComHet TIOD [61]

Glu799Lys USA 11 Hom TIOD [61]

Glu799Lys Netherlands 1 ComHet TIOD [13]

Glu799Lys Slovenia 1 ComHet MNG/Gardner syndrome [14]

Glu799Asp China 3 Het PH [35]

2413delC China (Taiwan) 1 ComHet TIOD [53]

Cys808fsX23 Portugal 1 ComHet goiter [40]

Cys808fsX23 Portugal 1 Hom goiter [40]

Cys808fsX23 Japan 1 Het goiter [15]

2422delT Netherlands 1 ComHet TIOD [13]

2422delT Turkey 1 Het n.d. [31]

2422delT China 1 Hom PH [18]

Cys808AlafsX24 Bosnia 2 ComHet goiter/Gardner syndrome [14]

Cys808AlafsX24 UK (+) 1 Hom PH [34]

Cys808AlafsX24 China 1 Hom PH [18]

Cys808AlafsX24 Russia 4 ComHet PH [37]

Cys808AlafsX24 Sudan 1 ComHet PH/goiter [47]

Cys808Arg Argentina 1 Het TIOD/goiter [9]

Cys808Arg Argentina 1 ComHet TIOD [38]

ins C2505-2511 Netherlands 1 ComHet TIOD [36]

ins C2505-2511 Netherlands 3 ComHet TIOD [13]

ins C2505-2511 Brazil 1 ComHet goiter/TIOD [10]

2512delT Netherlands 4 ComHet TIOD [13]

Cys838Ser Portugal 2 Hom goiter [40]

2519-19 G>C India 1 Het goiter [64]

Note. For designations, see Note to Table 1; n.d., not determined.

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

Table 5. Mutations in the TPO gene sequence encoding the TPO transmembrane domain (residues 846-871)

Mutation and/or change

in the TPO protein sequence

resulting from TPO mutations

Region,

country

n Mutation type Clinical manifestation

of hypothyroidism

Reference

Arg846Trp China 1 Het PH [35]

Arg846Trp China 2 Het PH/goiter [19]

Ser853Leu China 1 Het PH [19]

Gly860Arg Slovenia 1 ComHet MNG [14]

Gly860Arg Iran 1 Hom PH [20]

Gly860Arg China 1 ComHet PH [35]

Gly860Arg Sudan 1 Hom PH/goiter [46]

Note. For designations, see Note to Table 1.

a compound heterozygous variant among seven dif-

ferent TPO gene mutations in 15 patients from the

Netherlands  [36]. The same authors later expanded

their cohort to 45 patients to identify additional mu-

tations, including c.2422delT and c.2512delT [13].

A high incidence of severe hypothyroidism

caused by TIOD was observed in a younger genera-

tion of five related families within an inbred Amish

population. Sequencing identified two missense muta-

tions: Glu799Lys and Arg648Gln. The Glu799Lys mu-

tation was found in both alleles of 11 affected homo-

zygotes, while both mutations were present in each

of the three affected compound heterozygotes. These

findings highlight the effectiveness of DNA pooling

strategies for localizing defective genes in inbred

populations harboring two relatively rare mutations

[60]. Notably, the Glu799Lys mutation was also iden-

tified in one patient among a cohort of 30 patients

from Slovenia [14]. Analysis of the TPO gene in 14

unrelated patients presenting with clinical signs of

iodide organification disorder identified a single case

of the c.2422T>C mutation in exon  14 resulting in the

amino acid substitution Cys808Arg [9]. The same re-

search group from Argentina reported Cys808Arg as

a part of a compound heterozygous mutation in a pa-

tient with TIOD [38]. The Cys808fsX23 mutation has

been detected in various genetic contexts, including

heterozygous [15], compound heterozygous [40], and

homozygous states [18,  40]. Similarly, the c.2422delT

(p.Cys808AlafsX24) mutation has been reported as

compound heterozygous [13, 14, 37, 46] and homozy-

gous [18,  34]. The rare Cys838Ser mutation was iden-

tified in two twins with congenital goiter in Portugal

[40]. To evaluate the contribution of common genetic

variants in TSHR, TPO, TG, and DUOX2 genes to CH

associated with thyroid agenesis or goiter, a cohort of

1,144 newborns from India was screened. This study

identified a rare variant c.2519-19G>C (g.IVS14-19G>C

in intron  14 [64].

In conclusion, among the 13 mutations iden-

tified, five were homozygous: Glu799Lys (USA);

Cys808fsX23 and Cys838Ser (Portugal); and c.2422delT

(Cys808AlafsX24) (UK+, China). Ten mutations were

found in a compound heterozygous state. Notably,

four identical mutations were observed in patients

with CH from different regions worldwide: Glu799Lys

(Netherlands, USA, Slovenia); Cys808fsX23 (Portugal,

Japan); c.2422delT (Cys808AlafsX24) (Netherlands,

Turkey, Bosnia, UK+, Russia, China, Sudan); and

insC2505-2511 (Netherlands, Brazil).

Two mutations warrant special attention. The

missense Glu799Lys mutation has been identified in

17 patients with CH from three countries across two

continents: the Netherlands, the USA, and Slovenia.

Of these patients, 11 were homozygous and 6 were

compound heterozygous [13, 14, 36, 61]. MNG was

reported in one patient. The mutation was first de-

scribed in 1995 in a patient from the Netherlands[36].

The frameshift mutation c.2422delT (p.

Cys808AlafsX24), caused by a deletion in exon  14, was

identified in 12 patients with CH from seven coun-

tries across two continents: the Netherlands, Turkey,

Bosnia, the United Kingdom, Russia, China, and Su-

dan. Among these patients, three were homozygous

and eight were compound heterozygous for the mu-

tation. Goiter was observed in three patients [13, 14,

18, 34, 37, 46]. This mutation was first reported in

2000 in a patient from the Netherlands [13].

Mutations in the TPO transmembrane domain

(residues 846-871). The data on mutations in the

TPO transmembrane domain (residues 846-871) are

summarized in Table 5.

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

Table 6. Mutations in the TPO gene sequence coding for the intracellular domain (residues 872-933)

Mutation and/or change

in the TPO protein sequence

resulting from TPO mutations

Region,

country

n Mutation type Clinical manifestation

of hypothyroidism

Reference

2618+1G>T Russia 1 Het hypoplasia [37]

Pro883Ser Japan 1 Het PH [67]

2647C> T Malaysia 1 ComHet PH/goiter [48]

Pro883Ser China 1 ComHet goiter [49]

Pro883Ser China 1 Het PH [35]

Pro883Ser China 1 Het PH/athyreosis [19]

Pro883Ser China 1 Het goiter [19]

Pro883Ser China 1 ComHet PH [65]

Gly889Arg China 1 Het PH [19]

Gly889X China 1 ComHet goiter [49]

Arg908fsX USA n.d. n.d. n.d. [68]

Gln912fsX USA n.d. n.d. n.d. [68]

2748 G>A Portugal 2 ComHet PH [40]

Ser918Cysfs*62 Argentina 1 ComHet goiter [69]

del 10 bp 2812 Turkey 1 Hom MNG [70]

2749-2 A>C Argentina 1 ComHet goiter [69]

Glu917Lys USA n.d. n.d. n.d. [68]

Note. For designations, see Note to Table1; n.d., not determined.

Among 35 mutations identified in the TPO gene

during genomic analysis of 230 Chinese patients with

CH, two mutations (Arg846Trp and Gly860Arg) were

located in the transmembrane domain and were de-

tected in 23 individuals. The functional impact of

TPO mutations was assessed in  vitro by expressing 14

mutant TPO constructs in human embryonic kidney

(HEK) cells using the pcDNA3.1 plasmid. Notably, a

patient harboring the Gly860Arg mutation exhibited

the loss of thyroid function [35].

In a genome-wide study of 219 hypothyroid pa-

tients from northwest China, 17 individuals carried

19 rare variants of the TPO gene. Two of these muta-

tions were located within the transmembrane domain:

the previously reported Arg846Trp mutation and one

of seven newly identified variants Ser853Leu [19].

In a genomic study of 43 patients from Slovenia,

Bosnia, and Slovakia with persistent hypothyroidism

and orthotopic thyroid glands, representing 39 unre-

lated families, mutations in the TPO gene were identi-

fied in 20 patients. A total of seven distinct mutations

were detected, four of which were novel, including

Gly860Arg [14].

A mutation in the TPO gene was identified in

only one of 41 Iranian patients with PH. This muta-

tion causes the Gly860Arg substitution and was de-

tected in a homozygous state in the affected patient.

To further characterize this variant, SSCP analysis

and DNA sequencing of the corresponding TPO exon

were performed in the patient’s family, which showed

that both patient’s parents were heterozygous muta-

tion carriers [20].

Six TPO mutations were identified in affected

members of four families in the genomic analysis of

patients with CH and goiter from 26 Sudanese fami-

lies. One of these mutations, Gly860Arg located in the

transmembrane domain, was detected in a patient

in a homozygous state [46].

THYROID PEROXIDASE GENE MUTATIONS S413

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

In conclusion, only three heterozygous mutations

have been reported in the TPO transmembrane do-

main (residues 846-871). Among these, the missense

mutation Gly860Arg has been identified in patients

with CH from four countries (Iran, Sudan, Slovenia,

and China) spanning two continents. Reported cases

include two homozygous patients and two compound

heterozygotes. Clinically, one patient presented with

goiter, while another had MNG [14, 20, 35, 46]. The

Gly860Arg mutation was first described in 2007 in a

patient from Slovenia [14].

Mutations in the intracellular domain of TPO

(residues 872-933). The data on mutations in the TPO

intracellular domain are summarized in Table 6.

A rare splice site mutation, c.2618+1G>T

(g.IVS15+1G>T), was identified in intron 15 of the TPO

gene in a patient from Russia [37]. In a study of nine

Japanese children with transient thyroid dysfunction

or subclinical hypothyroidism detected by neona-

tal screening, one child was heterozygous for the

Arg450His mutation in TSHR, while another carried

a novel TPO mutation (Pro883Ser). No DUOX2 muta-

tions were detected in this cohort [66]. Identification

of the c.2647C>T mutation in a Malaysian patient [48]

was followed by multiple reports describing the same

mutation in five patients with CH from China [19, 35,

49, 64]. Molecular analysis of the DUOXA2 and TPO

genes in 30 Chinese children with CH identified six

TPO variants, including two heterozygous mutations

in the intracellular domain – Pro883Ser and Gly889X,

the latter representing a novel inactivating mutation.

Germline mutations identified in four unrelated fam-

ilies were consistent with an autosomal recessive

pattern of inheritance, while no DUOXA2 mutations

were detected [63]. Further analysis of 219 patients

with CH from northwestern China identified TPO

mutations in 17 individuals, including two mutations

affecting the intracellular domain (Pro883Ser and

Gly889Arg) [24]. In addition, a retrospective study

of ten Chinese patients with dyshormonogenesis re-

vealed heterozygous variants in two pathogenic genes

in each patient. Overall, pathogenic alterations were

identified in five genes (TSHR, TG, TPO, DUOX2, and

DUOXA2), all of which participate in the thyroid hor-

mone biosynthesis. In one patient, mutations were

detected in both the TPO (c.2647C>T; p.Pro883Ser)

and TG genes [64].

The summarized information on the hypothy-

roidism-associated mutations in TPO is available

in the ClinVar database. Currently, ClinVar reports

296 variants of the TPO gene sequence, 83 of which

are classified as pathogenic. The majority of identi-

fied variants are missense mutations (62.76%), fol-

lowed by synonymous substitutions (14.39%). Non-

sense mutations account for 1.55% of cases, while

frameshift mutations resulting from deletions and

insertions represent 0.67% and 0.38%, respectively.

Mutations most frequently associated with CH in-

clude c.2749G>A (p.Glu917Lys) in exon 17 and

several frameshift mutations in exon 16, namely

2736_2748+3delGGACTCGGAGCAGGT (Gln912fs) and

2723_2732delGGGCCGCAGC (Arg908fs) [67].

The c.2748G>A mutation was detected in two

patients from Portugal [40]. In a cohort of 17 Ar-

gentine patients with CH caused by thyroid dyshor-

monogenesis, rational clinical diagnostics led

to the identification of two novel TPO variants:

c.2749-2A>C (g.IVS16-2A>C) and c.2752_2753delAG

(p.Ser918Cysfs*62). Bioinformatic analysis and struc-

tural modeling were performed to predict the patho-

genic potential of the identified variants. Potential-

ly pathogenic biallelic variants of TPO and DUOX2

were detected in seven and two patients, respectively,

while potentially pathogenic monoallelic TPO variants

were identified in seven patients. Overall, 22 variants

were found to be associated with hypothyroidism.

All newly described mutations occur in the TPO re-

gions encoding domains critical for protein structure

and function and were predicted to result in a hypo-

thyroid phenotype [68].

A novel homozygous 10-bp deletion at position

2812 in exon 16 was identified in a patient from

Turkey. This frameshift mutation causes a profound

alteration of the protein intracellular domain and

represents the first reported mutation encoding inac-

tive TPO molecule with a severely disrupted intracel-

lular region. Histopathological analysis confirmed the

presence of dyshormonogenic goiter with multiple

follicular adenomas. The same deletion identified in

the DNA of leukocytes was also detected in the thy-

roid tissue cDNA, thus excluding transcript instabili-

ty or aberrant splicing as contributing mechanisms.

Both clinically unaffected parents were heterozygous

carriers of the mutation [69].

In conclusion, mutations in the intracellular do-

main of TPO are rare and typically occur as single

variants. Eleven reported mutations included one ho-

mozygous 10-bp deletion (del2812) identified in Tur-

key and three nonsense mutations: Gly889X (China),

Arg908fsX, and Gln912fsX (USA). Five of the identi-

fied mutations occurred in a compound heterozygous

state. Notably, the c.2647C>T (p.Pro883Ser) mutation

was detected in both heterozygous and compound

heterozygous states in seven cases, across patients

presenting with different hypothyroidism phenotypes.

CONCLUSION

Defects in dyshormonogenesis genes are the pre-

dominant cause of hereditary forms of CH. For in-

stance, molecular genetic analysis of patients with CH

ZUBKOV, BUTOVAS414

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

in Russia showed that such defects account for 84.0%

of cases. Among the identified monogenic variants,

the highest number of mutations were found in the

TPO gene (35.0%), including in patients with thyroid

hypoplasia [33].

In this study, 147 previously reported mutations

in the TPO gene were used as a reference to iden-

tify the most frequently occurring mutations in the

genomes of patients with CH across different regions

of the world. Twenty-four mutations were identified,

23 of which are located in the extracellular domain

of TPO: two in the 1-141 a.a. region, thirteen in the

MPO-like region, four in the CCP-like region, and four

in the EGF-like region. One mutation was found in

the transmembrane domain. Notably, the five mu-

tations observed in the largest number of carriers

(Ala397ProfsX76, Arg540X, Glu799Lys, Cys808AlafsX24,

and Gly860Arg) were located outside the IDR sequenc-

es identified using reference anti-TPO antibodies.

Regarding mutations within the IDR, particular

attention has been given to mutations in the regions

coding for two spatially proximate linear epitopes,

namely residues 606-617 and 706-720. These indi-

cated linear epitopes, one located in within IDR/A

region (a.a.  599-617) responsible for the interaction

with IDR/A-specific mAbs, and the other located

within a fragment (a.a.  713-717) of the discontinuous

IDR/B, are recognized by mAb1 from our panel of 36

mAbs and contribute to the formation of conforma-

tional epitope 3 on the TPO molecule. Autoantibod-

ies targeting the IDR/A fragment 606-617  a.a, recog-

nized by mAb1 are present in 82% of serum samples

from individuals with AITD. Autoantibodies against

conformational epitope 3 are detected in 96% of se-

rum samples from patients with the Graves’ disease

and in 100% of samples from patients with AIT [45].

According to the literature, the c.1851delC (p.Ser-

617Argfs23) mutation in the a.a.  606-617, fragment

was reported in a heterozygous and a compound

heterozygous states in two patients with CH without

goiter in Russia (2018) [33]. In the 706-722 region,

only one nonsense mutation, Phe718X, was reported

in a heterozygous state in a patient with TIOD in the

Netherlands (2000) [8].

Abbreviations

AIT autoimmune thyroiditis

AITD autoimmune thyroid disease

CH congenital hypothyroidism

IDR immunodominant region

MNG multinodular goiter

mAb monoclonal antibody

NGS next-generation sequencing

PH persistent hypothyroidism

PIOD partial iodide organification defect

SSCP single-strand conformation polymor-

phism

TIOD total iodide organification defect

TPO thyroid peroxidase

Contributions

A.V.Z. developed the concept, analyzed published

and research data; L.G.B. conducted literature search

and review.

Funding

This study was conducted within a framework of the

research project “Studying molecular mechanisms of

immunopathogenesis of allergic, autoimmune, and

infectious diseases for creating modern tools for pre-

diction, diagnosis, and treatment” (EGISU registration

no. 1023032400429-6-3.3.8; topic no. FGFS-2024-0008).

Ethics approval and consent to participate

This work does not contain studies involving human

or animal subjects.

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

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