Browsing by Author "Ribeiro, H."
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- Molecular and computational analyses of genes involved in mannose 6-phosphate independent traffickingPublication . Coutinho, M.F.; Lacerda, L.; Pinto, E.; Ribeiro, H.; Macedo-Ribeiro, S.; Castro, L.; Prata, M.J.; Alves, S.The newly-synthesized lysosomal enzymes travel to the trans-Golgi network (TGN) and are then driven to the acidic organelle. While the best-known pathway for TGN-to-endosome transport is the delivery of soluble hydrolases by the M6P receptors (MPRs), additional pathways do exist, as showed by the identification of two alternative receptors: LIMP-2, implicated in the delivery of β-glucocerebrosidase; and sortilin, involved in the transport of the sphingolipid activator proteins prosaposin and GM2AP, acid sphingomyelinase and cathepsins D and H. Disruption of the intracellular transport and delivery pathways to the lysosomes may result in lysosomal dysfunction, predictably leading to a range of clinical manifestations of lysosomal storage diseases. However, for a great percentage of patients presenting such manifestations, no condition is successfully diagnosed. To analyse if, in this group, phenotypes could be determined by impairments in the known M6P-independent receptors, we screened the genes that encode for LIMP-2 and sortilin. No pathogenic mutations were identified. Other approaches will be needed to clarify whether sortilin dysfunction may cause disease.
- SCARB2 mutations as modifiers in Gaucher disease: the wrong enzyme at the wrong place?Publication . Coutinho, Maria Francisca; Lacerda, L.; Gaspar, A.; Pinto, E.; Ribeiro, I.; Laranjeira, F.; Ribeiro, H.; Silva, E.; Ferreira, C.; Prata, M.J.; Alves, S.Unlike most lysosomal proteins, β-glucocerebrosidase (GCase), the hydrolase defective in Gaucher disease (GD), is delivered to lysosomes through its interaction with the transmembrane protein LIMP2. A few years ago, mutations in its coding gene, SCARB2, were reported to modify the severity of GD phenotype. The existence of a great variety of GD phenotypes is well-known, with numerous patients who carry identical genotypes presenting remarkable phenotypic variability. Over the years, that variability has been attributed to other genetic, epigenetic and/or environmental factors. Still, there is still much to learn on this subject. Recently, an association between Parkinson's disease (PD) and the presence of mutations in the GBA gene has been demonstrated. Moreover, there are also studies suggesting that genetic variants in the SCARB2 gene may also be risk factors for PD. We analysed the SCARB2 gene in the Portuguese cohort of 91 GD patients, having identified 3 different SCARB2 coding variants. Of those, 2 were known polymorphisms with high prevalence in the normal population (p.M159V and p.V396I) and the third was a novel coding variant, p.T398M, present in heterozigousity in a single patient. Our study demonstrated that, at least for the Portuguese population, genetic variability at SCARB2 does not account much to the GD phenotypic spectrum. Nevertheless, in vitro analyses of the novel p.T398M are envisaged, in order to further characterize the effect of this variant on the levels and sub-cellular location of GCase. The clinical presentation of the patient harbouring this coding variant will also be discussed.
- SCARB2 mutations as modifiers in Gaucher disease: the wrong enzyme at the wrong place?Publication . Coutinho, M.F.; Lacerda, L.; Gaspar, A.; Pinto, E.; Ribeiro, I.; Laranjeira, F.; Ribeiro, H.; Silva, E.; Ferreira, C.; Prata, M.J.; Alves, S.Unlike most lysosomal proteins, β-glucocerebrosidase (GCase), the hydrolase defective in Gaucher disease (GD), is delivered to lysosomes through its interaction with the transmembrane protein LIMP2. A few years ago, mutations in its coding gene, SCARB2, were reported to modify the severity of GD phenotype. The existence of a great variety of GD phenotypes is well-known, with numerous patients who carry identical genotypes presenting remarkable phenotypic variability. Over the years, that variability has been attributed to other genetic, epigenetic and/or environmental factors. Still, there is still much to learn on this subject. Recently, an association between Parkinson's disease (PD) and the presence of mutations in the GBA gene has been demonstrated. Moreover, there are also studies suggesting that genetic variants in the SCARB2 gene may also be risk factors for PD. We analysed the SCARB2 gene in the Portuguese cohort of 91 GD patients, having identified 3 different SCARB2 coding variants. Of those, 2 were known polymorphisms with high prevalence in the normal population (p.M159V and p.V396I) and the third was a novel coding variant, p.T398M, present in heterozigousity in a single patient. Our study demonstrated that, at least for the Portuguese population, genetic variability at SCARB2 does not account much to the GD phenotypic spectrum. Nevertheless, in vitro analyses of the novel p.T398M are envisaged, in order to further characterize the effect of this variant on the levels and sub-cellular location of GCase. The clinical presentation of the patient harbouring this coding variant will also be discussed.