Five novel inactivating mutations in the thyroid peroxidase gene responsible for congenital goiter and iodide organification defect

Abstract

Thyroid peroxidase (TPO) defects, typically transmitted as autosomal recessive traits, result in hypothyroid goiters with failure to convert iodide into organic iodine. We analyzed the TPO gene in 14 unrelated patients with clinical evidence of iodide organification defects. Seven of the affected individuals harbored mutations in the TPO gene; one was compound heterozygous, the others were simply heterozygous for TPO mutations. Five novel mutations have been identified, one of which was found to be a single nucleotide deletion, while the other four were single nucleotide substitutions. A frameshift mutation c.387delC was detected in exon 5 which leads to an early termination signal in exon 7 (p.N129fsX208). Two missense mutations were identified in exon 8. The first, a c.920A>C transversion that results in a p.N307T substitution, was found in two patients. The second, a c

High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis

“…In other studies, single TPO mutations were detected in only about 20% of patients with TIOD (7,22,40,41). One report of mRNA analysis after thyroidectomy in a patient with TIOD and a single allele mutation proved a lack of expression of the other allele with a normal reading frame.…”

“…This short amino acid sequence is partly conserved among other mammalian peroxidases, as shown in Table 3. Several other mutations causing TIOD have been identified in close proximity by other groups -I447F, Y453D, L458P, R491H, G493S, and P499L (13,19,20,22,25). Exons 8, 9 and 10 encode for the catalytic part of the enzyme and are the most frequent locations of inactivating mutations.…”

“…The TPO gene spans over 150 kb on the short arm of chromosome 2, locus 2p25, and consists of 17 exons (9,10). Published molecular genetic studies suggest that TPO gene mutations are one of the most common causes of thyroid dyshormonogenesis, with several different inactivating mutations being identified in patients with total iodide organification defects (TIOD; (7,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)). The inheritance is autosomal recessive (16,29).…”

Genetic analysis of thyroid peroxidase (<i>TPO</i>) gene in patients whose hypothyroidism was found in adulthood in West Bengal, India

“…TPO is a membrane-bound glycoprotein (102 kDa), found as a dimer [15]. TPO mutations are typically inherited as autosomal recessive traits [16].…”

“…TPO being a key enzyme for thyroid hormone synthesis, TPO gene defect (especially non-synonymous cSNPs) can potentially lead to severe defects in thyroid hormone production, due to total iodide organification defects (TIOD) or partial iodide organification defects (PIOD). Screening and identification of mutations in the TPO gene of patients with evidence of TIOD and PIOD has been done by several groups in different countries of the world like Argentina [16], Netherlands [12], Japan [27], Brazil [25], Portugal [28], and China [29]. Majority of the studies related to TPO gene defect was centered on congenital hypothyroidism but our study was based on hypothyroidism detected in adulthood as we tried to evaluate the other potential causes of this disease in this population besides autoimmunity and iodine deficiency.…”