RESUMO
Molecular defects in the gene encoding the enzyme iduronate-2-sulfatase (IDS) result in Hunter disease (mucopolysaccharidosis type II, MPS II). To determine the molecular basis of MPS II in Thailand, the IDS gene was analysed in 20 Thai patients with Hunter syndrome from 18 unrelated families. A total of 19 different mutations, including 9 missense mutations, 3 nonsense mutations, 3 splice site alterations, 1 deletion, 2 indels, and 1 rearrangement were identified, 8 of which were novel (p.R101C, p.D148V, p.G224A, p.K227E, p.E254X, p.W337X, c.440_442delinsTT and c.720_731delinsTTTCAGATGTTCTCCCCAG). Evaluation of the IDS activity of two hemizygous variants identified in the same patient, p.R101C and p.R468Q, by expression of IDS with the individual mutations in COS 7 cells indicated that only the p.R468Q mutation affected IDS protein activity. Two exonic mutations, c.257C>T (p.P86L) and c.418G>A, were found to activate multiple cryptic splice sites, resulting in aberrantly spliced transcripts. Thus, MPS II in Thailand is caused by a diverse set of defects affecting both IDS protein production and activity.
Assuntos
Testes Genéticos , Glicoproteínas/genética , Mucopolissacaridose II/enzimologia , Mucopolissacaridose II/genética , Mutação , Processamento Alternativo , Animais , Povo Asiático/genética , Células COS , Estudos de Casos e Controles , Criança , Pré-Escolar , Chlorocebus aethiops , Códon sem Sentido , Análise Mutacional de DNA , Rearranjo Gênico , Predisposição Genética para Doença , Testes Genéticos/métodos , Glicoproteínas/metabolismo , Hemizigoto , Humanos , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose II/etnologia , Mutação de Sentido Incorreto , Fenótipo , Deleção de Sequência , Índice de Gravidade de Doença , Tailândia/epidemiologia , TransfecçãoRESUMO
Gaucher disease is an autosomal recessive lysosomal storage disorder due to deficiency of the lysosomal enzyme glucocerebrosidase. Three clinical phenotypes, type 1, nonneuronopathic; and types 2 and 3, acute and subacute neuronopathic are recognized. The incidence of Gaucher disease in the Thai population is unknown, but likely under-diagnosed. We performed molecular analysis in four patients, from three sibships, with type 3 Gaucher disease. Four mutant glucocerebrosidase (GBA) alleles were identified including two novel splice site mutations, IVS6-1G>C and IVS9-3C>G; both are predicted to result in truncated protein products, p.F255fsX256, and p.K464fsX487 and p.S463fsX480, respectively. One patient, homozygous for the L444P point mutation, had a "Norbottnian-like" phenotype, with more severe visceral involvement, kyphosis, barreled chest, and no neurological involvement other than supranuclear gaze palsy. These molecular studies of neuronopathic Gaucher disease will provide additional genotype-phenotype correlation particularly in non-Caucasian population.
