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Authors
Abstract(s)
Introdução: A síndrome de hipoparatiroidismo, surdez e displasia renal (HDR -
Hypoparathyroidism, Deafness and Renal dysplasia) é uma endocrinopatia autossómica
dominante com origem em mutações inativadoras do gene GATA3 (GATA binding protein 3).
O gene GATA3, localizado no cromossoma 10p14-15, codifica um fator de transcrição que
regula a expressão de genes envolvidos no desenvolvimento embrionário. A síndrome HDR é
muito rara, havendo apenas cerca de 100 famílias descritas na literatura mundial.
Doentes e métodos: Estudou-se um doente do sexo masculino com hipoparatiroidismo
primário diagnosticado aos 51 anos de idade na sequência da investigação de uma crise
convulsiva por hipocalcémia. Apresentava ainda uma insuficiência renal crónica de estadio
3b, de duração indeterminada, e uma surdez neurosensorial congénita. Como antecedentes
familiares, apresentava o pai com surdez congénita, falecido aos 69 anos de idade com
insuficiência renal. Para o estudo genético procedeu-se ao isolamento do ácido
desoxirribonucleico (DNA) genómico do propositus, à amplificação dos exões 2 a 6 do gene
GATA3 por reação de polimerização em cadeia (PCR) e à análise das respetivas sequências
por sequenciação automatizada.
Resultados: A sequenciação do gene GATA3 revelou uma inserção de quatro nucleótidos
(CAAG), no exão 3, entre as posições 357 e 358 da sequência do respetivo DNA
complementar (cDNA) (c.357_358insCAAG). Esta mutação estava presente em heterozigotia
e foi confirmada através da análise de heteroduplexes.
Discussão e conclusão: A mutação c.357_358insCAAG, identificada no gene GATA3,
condiciona uma alteração do tipo frameshift com a introdução de um codão de terminação
prematuro e produção de uma proteína truncada. A haploinsuficiência, decorrente da perda
funcional de um dos alelos GATA3, tem como consequência provável a alteração da
transcrição de genes importantes para o desenvolvimento das paratiróides, rins e ouvido
interno. Esta mutação, até ao momento atual, ainda não se encontra descrita e alarga o
espectro de mutações implicadas em casos de síndrome HDR.
Introduction: The Hypoparathyroidism, Deafness and Renal dysplasia (HDR) syndrome is an autosomal dominant endocrinopathy caused by inactivating mutations in the GATA3 gene. The GATA3 gene which is located on chromosome 10p14-15 and encodes a transcription factor that regulates the expression of genes involved in embryonic development. The HDR syndrome is very rare with only about 100 families reported in the literature. Patients and methods: We studied a man with primary hypoparathyroidism diagnosed at 51 years of age, after the investigation of a seizure crisis due to hypocalcaemia. He also presented a stage 3b chronic kidney disease, and a neurosensorial congenital deafness. As family history, his father presented congenital deafness, and died at 69 years of age with chronic kidney disease. For the genetic study, we proceeded to the isolation of genomic deoxyribonucleic acid (DNA) of the patient, the amplification of exons 2 to 6 of the GATA3 gene by polymerase chain reaction (PCR) and analysis of the sequences by automated sequencing. Results: The sequencing of the GATA3 gene showed an insertion of four nucleotides (CAAG) in exon 3, between the positions 357 and 358 of the cDNA sequence (c.357_358insCAAG). This mutation was present in heterozygosity and was confirmed by analysis of heteroduplexes. Discussion and conclusion: The c.357_358insCAAG mutation, identified in the GATA3 gene, determines a frameshift change with the introduction of a premature termination codon and the production of a truncated protein. The haploinsufficiency due to functional loss of one GATA3 allele is likely to change the transcription of genes important for the development of the parathyroids, kidneys and inner ear. This mutation, until now, has not yet been described and extends the spectrum of mutations involved in cases of HDR syndrome.
Introduction: The Hypoparathyroidism, Deafness and Renal dysplasia (HDR) syndrome is an autosomal dominant endocrinopathy caused by inactivating mutations in the GATA3 gene. The GATA3 gene which is located on chromosome 10p14-15 and encodes a transcription factor that regulates the expression of genes involved in embryonic development. The HDR syndrome is very rare with only about 100 families reported in the literature. Patients and methods: We studied a man with primary hypoparathyroidism diagnosed at 51 years of age, after the investigation of a seizure crisis due to hypocalcaemia. He also presented a stage 3b chronic kidney disease, and a neurosensorial congenital deafness. As family history, his father presented congenital deafness, and died at 69 years of age with chronic kidney disease. For the genetic study, we proceeded to the isolation of genomic deoxyribonucleic acid (DNA) of the patient, the amplification of exons 2 to 6 of the GATA3 gene by polymerase chain reaction (PCR) and analysis of the sequences by automated sequencing. Results: The sequencing of the GATA3 gene showed an insertion of four nucleotides (CAAG) in exon 3, between the positions 357 and 358 of the cDNA sequence (c.357_358insCAAG). This mutation was present in heterozygosity and was confirmed by analysis of heteroduplexes. Discussion and conclusion: The c.357_358insCAAG mutation, identified in the GATA3 gene, determines a frameshift change with the introduction of a premature termination codon and the production of a truncated protein. The haploinsufficiency due to functional loss of one GATA3 allele is likely to change the transcription of genes important for the development of the parathyroids, kidneys and inner ear. This mutation, until now, has not yet been described and extends the spectrum of mutations involved in cases of HDR syndrome.
Description
Keywords
Endocrinologia Gene Gata3 Genética Mutação Síndrome Hdr