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

2011-03-01Journal article Restricted access
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dc.contributor.authorCoutinho, Maria Francisca
dc.contributor.authorLacerda, Lúcia
dc.contributor.authorMacedo-Ribeiro, Sandra
dc.contributor.authorBaptista, Estela
dc.contributor.authorRibeiro, Helena
dc.contributor.authorPrata, Maria João
dc.contributor.authorAlves, Sandra
dc.date.accessioned2011-10-31T11:18:51Z
dc.date.available2011-10-31T11:18:51Z
dc.date.issued2011-03-01
dc.description.abstractThe 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.por
dc.identifier.citationClin Genet. 2011 Jan 10. doi: 10.1111/j.1399-0004.2011.01625.x. [Epub ahead of print]por
dc.identifier.otherESSN:1399-0004
dc.identifier.urihttp://hdl.handle.net/10400.18/308
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherJohn Wiley and Sonspor
dc.relationComissão de Fomento da Investigação em Cuidados de Saúde I.P, no. 100/2007por
dc.relation.publisherversionhttp://onlinelibrary.wiley.com/doi/10.1111/j.1399-0004.2011.01625.x/fullpor
dc.subjectGalactosialidosispor
dc.subjectGenotype – phenotype correlationpor
dc.subjectGM1 gangliosidosispor
dc.subjectLysosomal multienzyme complexpor
dc.subjectLysosomal storage disorderspor
dc.subjectMutational spectrumpor
dc.subjectSialidosispor
dc.subjectDoenças Genéticaspor
dc.titleLysosomal multienzymatic complex-related diseases: a genetic study among Portuguese patientspor
dc.typejournal article
dspace.entity.typePublication
oaire.citation.titleClinical Geneticspor
rcaap.rightsrestrictedAccesspor
rcaap.typearticlepor

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