Lysosomal multienzymatic complex-related diseases: a genetic study among Portuguese patients

• Tipo: Artigo em Revista Científica Internacional
• Data: 2012

Autores

Coutinho, MF (Autor) Outra; Lacerda, L (Autor) Outra; Macedo Ribeiro, S (Autor) Outra; Baptista, E (Autor) Outra; Ribeiro, H (Autor) Outra; Prata, MJ (Autor) FCUP; Alves, S (Autor) Outra

Revista

Título: Clinical Genetics

Vol. 81

Páginas: 379-393

ISSN: 0009-9163

Editora: Wiley-Blackwell

Indexação

ISI Web of Knowledge - 9 Citações

Scopus - 12 Citações

Classificação Científica

FOS: Ciências exactas e naturais > Ciências da terra e ciências do ambiente

Outras Informações

ID Authenticus: P-002-BPJ

DOI: 10.1111/j.1399-0004.2011.01625.x

Abstract (EN): The functional activity of lysosomal enzymes sialidase, beta-galactosidase and N-acetylaminogalacto-6-sulfate-sulfatase in the cell depends on their association in a multienzyme complex with cathepsin A. Mutations in any of the components of this complex result in functional deficiency thereby causing severe lysosomal storage disorders. Here, we report the molecular defects underlying sialidosis (mutations in sialidase; gene NEU1), galactosialidosis (mutations in cathepsin A; gene PPGB) and GM1 gangliosidosis (mutations in beta-galactosidase; gene GLB1) in Portuguese patients. We performed molecular studies of the PPGB, NEU1 and GLB1 genes in biochemically diagnosed Portuguese patients. Gene expression was determined and the effect of each mutation predicted at protein levels. In the NEU1 gene, we found three novel missense mutations (p. P200L, p. D234N and p. Q282H) and one nonsense mutation (p. R341X). In the PPGB gene, we identified two missense mutations, one novel (p. G86V) and one already described (p. V104M), as well as two new deletions (c. 230delC and c. 991-992delT) that give rise to non-functional proteins. We also present the first molecular evidence of a causal missense mutation localized to the cathepsin A active site. Finally, in the GLB1 gene, we found six different mutations, all of them previously described (p. R59H, p. R201H, p. H281Y, p. W527X, c. 1572-1577InsG and c. 845-846delC). Seven novel mutations are reported here, contributing to our knowledge of the mutational spectrum of these diseases and to a better understanding of the genetics of the lysosomal multienzymatic complex. The results of this study will allow carrier detection in affected families and prenatal molecular diagnosis, leading to the improvement of genetic counseling.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 15