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Title: Lysosomal multienzymatic complex-related diseases: a genetic study among Portuguese patients
Author: Coutinho, Maria Francisca
Lacerda, Lúcia
Macedo-Ribeiro, Sandra
Baptista, Estela
Ribeiro, Helena
Prata, Maria João
Alves, Sandra
Keywords: Galactosialidosis
Genotype – phenotype correlation
GM1 gangliosidosis
Lysosomal multienzyme complex
Lysosomal storage disorders
Mutational spectrum
Doenças Genéticas
Issue Date: 1-Mar-2011
Publisher: John Wiley and Sons
Citation: Clin Genet. 2011 Jan 10. doi: 10.1111/j.1399-0004.2011.01625.x. [Epub ahead of print]
Abstract: The functional activity of lysosomal enzymes sialidase, β-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 β-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.
Peer review: yes
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Appears in Collections:DGH - Artigos em revistas internacionais

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