Missense Mutation (C1263R) in the Thyroglobulin Gene Causes Congenital Goiter with Mild Hypothyroidism by Impaired Intracellular Transport.

Context: Most patients with defective synthesis and/or secretion of thyroglobulin (Tg) present relatively high serum free T 3 (FT 3 ) concentrations with disproportionately low free T 4 (FT 4 ) resulting in a high FT 3 /FT 4 ratio. The mechanism of this change in FT 3 /FT 4 ratio remains unknown.Objective: We hypothesize that increased type 2 iodothyronine deiodinase (D2) activity in the thyroid gland may explain the higher FT 3 /FT 4 ratio that is frequently observed in patients with abnormal Tg synthesis.

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“…These findings are consistent with those observed in a case of defective intracellular transport of Tg (Fig. 2B) (14).…”

Section: Morphological and Biochemical Analysis Of The Thyroid Of Patsupporting

confidence: 93%

Thyroglobulin Gene Mutations Producing Defective Intracellular Transport of Thyroglobulin Are Associated with Increased Thyroidal Type 2 Iodothyronine Deiodinase Activity

Kanou

Hishinuma

Tsunekawa

et al. 2007

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…Histological studies pointed to abnormal protein trafficking from endoplasmic reticulum to Golgi, which is a frequent consequence of Tg gene mutations (14). We have shown that Tg mutations, C1245R and C1977S, which perturb correct folding of Tg protein, caused impaired intracellular transport, leading to accumulation of abnormal Tg in endoplasmic reticulum (9,15,16). The mutation C1058R also caused defects in intracellular transport as shown by carbohydrate analysis of Tg protein and increased expression of molecular chaperones in the patients' thyroid (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Haplotype Analysis Reveals Founder Effects of Thyroglobulin Gene Mutations C1058R and C1977S in Japan

Hishinuma¹,

Fukata

Nishiyama

et al. 2006

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…One of these patients was euthyroid, the other individual had mild hypothyroidism, but both had undetectable TG levels. As demonstrated by sensitivity to digestion with endoglycosidase H and formation of high molecular aggregates, this mutation is retained in the ER (84,85).…”

Section: Tg Gene Mutations In Humansmentioning

confidence: 95%

“…Two unrelated patients with congenital goiter were found to be homozygous for a point mutation (c.3790T>C; originally described as c.3787T>C) leading to substitution of cysteine 1264 in the precursor by arginine (84,85). One of these patients was euthyroid, the other individual had mild hypothyroidism, but both had undetectable TG levels.…”

Section: Tg Gene Mutations In Humansmentioning

confidence: 99%

Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism

Vono-Toniolo

Kopp

2004

Arq Bras Endocrinol Metab

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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

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Missense Mutation (C1263R) in the Thyroglobulin Gene Causes Congenital Goiter with Mild Hypothyroidism by Impaired Intracellular Transport.

Abstract: Abstract.Metabolic abnormalities in thyroid hormonogenesis cause congenital goiter. Here we studied a case of mild hypothyroidism caused by a novel missense mutation in the thyroglobulin (TG) gene.

Cited by 27 publications

References 32 publications

Thyroglobulin Gene Mutations Producing Defective Intracellular Transport of Thyroglobulin Are Associated with Increased Thyroidal Type 2 Iodothyronine Deiodinase Activity

Thyroglobulin Gene Mutations Producing Defective Intracellular Transport of Thyroglobulin Are Associated with Increased Thyroidal Type 2 Iodothyronine Deiodinase Activity

Haplotype Analysis Reveals Founder Effects of Thyroglobulin Gene Mutations C1058R and C1977S in Japan

Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism

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