Mutation screening of the thyroid peroxidase gene in a cohort of 55 Portuguese patients with congenital hypothyroidism

Abstract

Objective: Defects in the human thyroid peroxidase (TPO) gene are reported to be one of the causes of congenital hypothyroidism (CH) due to a total iodide organification defect. The aim of the present study was to determine the nature and frequency of TPO gene mutations in patients with CH, characterised by elevated TSH levels and orthotopic thyroid gland, identified in the Portuguese National Neonatal Screening Programme. Subjects and methods: The sample comprised 55 patients, from 53 unrelated families, with follow-up in the endocrinology clinics of the treatment centres of Porto and Lisbon. Mutation screening in the TPO gene (exons 1-17) was performed by single-strand conformational analysis followed by sequencing of fragments with abnormal migration patterns. Results: Eight different mutations were detected in 13 patients (seven homozygotes and six compound heterozygotes). Novel mutations included three missense mutations, namely 391T . C (S131P), 1274A . G (N425S) and 2512T . A (C838S), as well as the predictable splice mutation 2748G . A (Q916Q/spl?). The undocumented polymorphism 180-47A . C was also detected. Conclusion:The results are in accordance with previous observations confirming the genetic heterogeneity of TPO defects. The proportion of patients in which the aetiology was determined justifies the implementation of this molecular testing in our CH patients with dyshormonogenesis.

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

“…The prevalence of TPO gene mutations in the studied population (46%) was higher than that noted in a Portuguese study, where similar inclusion criteria, without the determination of the iodide organification defect, were used and mutations identified in 24% of patients (24). While the percentage of dyshormonogenesis (34%) in the Slovene population is higher than the 15% reported in other studies (2, 7), the estimated incidence of CH due to TPO gene mutations of 1:20 000 newborns is also considerably higher when compared with the published estimate in the Dutch population, where the calculated incidence of TIOD is 1:66 000 newborns (7).…”

“…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 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.…”

Review Article on Congenital Hypothyroidism and Newborn Screening Program in Africa; the Present Situation and the Way Forward

“…Most of them are inherited in an autosomal recessive manner, which means that the risk of recurrence is put at 25% for subsequent pregnancies. Thyroid peroxidase (TPO) deficiency is the commonest in this etiologic group, in a recent study TPO gene mutations were found in 25% of patients with CH and eutopic gland [14]. The genetic mutations implicated in dyshormonogenesis are DUOX2, TPO, Tg, NIS, THOX-2.…”