Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism

Abstract

Congenital hypothyroidism affects about 1:3000-1:4000 infants. Screening programs now permit early recognition and treatment, thus avoiding the disastrous consequences of thyroid hormone deficiency on brain development. In about 85%, congenital hypothyroidism is associated with developmental defects referred to as thyroid dysgenesis. They include thyroid (hemi)agenesis, ectopic tissue and thyroid hypoplasia. Thyroid dysgenesis is usually sporadic; in only 2% it occurs in a familial fashion. It can be caused by mutations in transcription factors that are essential for the development and function of thyroid follicular cells. Thyroid hypoplasia can also result from resistance to TSH at the level of the thyrocytes. Defects in the steps required for thyroid hormone synthesis within thyroid follicular cells are referred to as dyshormonogenesis and account for about 10-15% of congenital hypothyroidism. In contrast to thyroid dysgenesis, affected patients typically present with goitrous enlargement of the thyroid. The defects leading to dyshormonogenesis typically display a recessive mode of inheritance. Careful clinical, biochemical and molecular analyses of patients with syndromic and nonsyndromic forms of thyroid dysgenesis and dyshormonogenesis have significantly enhanced our understanding of the wide spectrum of pathogenetic mechanisms underlying congenital hypothyroidism and provide unique insights into the (patho)physiology of thyroid development and hormone synthesis. RESUMO Mutações no Gene da Tireoglobulina e Outros Defeitos Genéticos Associados Com Hipotireoidismo Congênito.Hipotireoidismo congênito afeta cerca de 1:3.000-1:4.000 recém-nascidos. Atualmente, programas de triagem neonatal permitem o reconhecimento e tratamento precoces, evitando suas conseqüências desastrosas no desenvolvimento cerebral. Em cerca de 85% dos pacientes, o hipotireoidismo congênito está associado à defeitos no desenvolvimento da tireóide referidos como disgenesia tireoideana. A disgenesia tireoideana ocorre geralmente de forma esporádica; somente 2% dos casos apresentam caráter familial. Podem ser causados por mutações nos fatores de transcrição que são essenciais para o desenvolvimento e função das células foliculares tireoideanas. Hipoplasia da tireóide pode também resultar de resistência tireoideana ao TSH. Defeitos na síntese dos hormônios tireoideanos são referidos como disormonogênese tireoideana e concorrem para 10-15% dos casos de hipotireoidismo congênito. Os pacientes usualmente apresentam bócio, ao contrário da disgenesia tireoideana. Tipicamente, os defeitos que causam disormonogênese apresentam herança recessiva. Uma série de estudos recentes aumentou significativamente nosso entendimento dos mecanismos patogênicos do hipotireoidismo congênito, oferecendo

A Rare Case of Recurrent Fetal Goiter

“…The possible candidate genes of dyshormonogenesis are: (1) thyroid peroxidase (TPO) gene; (2) thyroglobulin (TG) gene; (3) sodium iodide symporter (NIS) gene; (4) pendrin (PDS) gene, and (5) thyroid oxidase 2 (THOX2) gene [15] . Most of these mutations follow a recessive mode of inheritance [16] . We could not do testing for genetic basis of congenital hypothyroidism in our case.…”

Insights into the posttranslational structural heterogeneity of thyroglobulin and its role in the development, diagnosis, and management of benign and malignant thyroid diseases

“…In practice, this could really be a problem in view of recent studies that found two phenomena that may change the primary polypeptide sequence of Tg: different singlenucleotide polymorphisms in the Tg gene leading to an amino acid exchange (60) and somatic mutations in tumor cells (2.7%) in a significant number of patients with DTC (61). Tg gene may carry several polymorphisms and some of them have been associated with autoimmune thyroid disease (62). Besides, different TG RNA splicing forms from different human thyroid tissues have also been described in tumor samples and this kind of variation seems to be of high frequency, even in normal thyroid tissue (63).…”

Congenital hypothyroidism: From paracelsus to molecular diagnosis

“…In 1991, Ieri et al [59] were the first to report a hypothyroid patient with goiter who turned out to be homozygous for an autosomal recessive intronic mutation of the Tg gene that led to a complete deletion of an important tyrosinedonor region. Other cases of goitrous hypothyroidism, all inherited as autosomal recessive traits and implicating different mutation sites on the Tg gene have been reviewed recently [60].…”