Iodide Transport Defect: Functional Characterization of a Novel Mutation in the Na(+)/I(-) Symporter 5 `-Untranslated Region in a Patient with Congenital Hypothyroidism
Contribuinte(s) |
UNIVERSIDADE DE SÃO PAULO |
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Data(s) |
20/10/2012
20/10/2012
2011
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Resumo |
Context: Iodide transport defect (ITD) is an autosomal recessive disorder caused by impaired Na(+)/I(-) symporter (NIS)-mediated active iodide accumulation into thyroid follicular cells. Clinical manifestations comprise a variable degree of congenital hypothyroidism and goiter, and low to absent radioiodide uptake, as determined by thyroid scintigraphy. Hereditary molecular defects in NIS have been shown to cause ITD. Objective: Our objective was to perform molecular studies on NIS in a patient with congenital hypothyroidism presenting a clinical ITD phenotype. Design: The genomic DNA encoding NIS was sequenced, and an in vitro functional study of a newly identified NIS mutation was performed. Results: The analysis revealed the presence of an undescribed homozygous C to T transition at nucleotide -54 (-54C>T) located in the 5`-untranslated region in the NIS sequence. Functional studies in vitro demonstrated that the mutation was associated with a substantial decrease in iodide uptake when transfected into Cos-7 cells. The mutation severely impaired NIS protein expression, although NIS mRNA levels remained similar to those in cells transfected with wild-type NIS, suggesting a translational deficiency elicited by the mutation. Polysome profile analysis demonstrated reduced levels of polyribosomes-associated mutant NIS mRNA, consistent with reduced translation efficiency. Conclusions: We described a novel mutation in the 5`-untranslated region of the NIS gene in a newborn with congenital hypothyroidism bearing a clinical ITD phenotype. Functional evaluation of the molecular mechanism responsible for impaired NIS-mediated iodide concentration in thyroid cells indicated that the identified mutation reduces NIS translation efficiency with a subsequent decrease in protein expression and function. (J Clin Endocrinol Metab 96: E1100-E1107, 2011) Fondo Nacional de Ciencia y Tecnologia (FONCyT) Fondo Nacional de Ciencia y Tecnologia (FONCyT) Secretaria de Ciencia y Tecnologia de la Universidad Nacional de Cordoba (SeCyT) Secretaria de Ciencia y Tecnologia de la Universidad Nacional de Cordoba (SeCyT) Agencia Cordoba Ciencia Agencia Cordoba Ciencia Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Conselho Nacional de Pesquisa e Desenvolvimento (CNPq) |
Identificador |
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v.96, n.7, p.E1100-E1107, 2011 0021-972X http://producao.usp.br/handle/BDPI/27894 10.1210/jc.2011-0349 |
Idioma(s) |
eng |
Publicador |
ENDOCRINE SOC |
Relação |
Journal of Clinical Endocrinology & Metabolism |
Direitos |
restrictedAccess Copyright ENDOCRINE SOC |
Palavras-Chave | #SODIUM/IODIDE SYMPORTER #CYSTIC-FIBROSIS #MESSENGER-RNA #TRANSLATION INITIATION #THYROID-FUNCTION #GENE-EXPRESSION #MECHANISM #DISEASE #GLAND #NIS #Endocrinology & Metabolism |
Tipo |
article original article publishedVersion |