Browsing by Author "Gaspar, A."
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- Retrospective study of the medium-chain acyl-CoA dehydrogenase deficiency in PortugalPublication . Ventura, F.V.; Leandro, P.; Luz, A.; Rivera, I.A.; Silva, M.F.; Ramos, R.; Rocha, H.; Lopes, A.; Fonseca, H.; Gaspar, A.; Diogo, L.; Martins, E.; Leão-Teles, E.; Vilarinho, L.; Tavares de Almeida, I.Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the commonest genetic defect of mitochondrial fatty acid β-oxidation. About 60% of MCADD patients are homozygous for the c.985A>G (p.Lys329Glu) mutation in the ACADM gene (G985 allele). Herein, we present the first report on the molecular and biochemical spectrum of Portuguese MCADD population. From the 109 patients studied, 83 were diagnosed after inclusion of MCADD in the national newborn screening, 8 following the onset of symptoms and 18 through segregation studies. Gypsy ancestry was identified in 85/109 patients. The G985 allele was found in homozygosity in 102/109 patients, in compound heterozygosity in 6/109 and was absent in one patient. Segregation studies in the Gypsy families showed that 93/123 relatives were carriers of the G985 allele, suggesting its high prevalence in this ethnic group. Additionally, three new substitutions-c.218A>G (p.Tyr73Cys), c.503A>T (p.Asp168Val) and c.1205G>T (p.Gly402Val)-were identified. Despite the particularity of the MCADD population investigated, the G985 allele was found in linkage disequilibrium with H1(112) haplotype. Furthermore, two novel haplotypes, H5(212) and H6(122) were revealed.
- 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.
- Trimethylaminuria (fish odor syndrome): genotype characterization among Portuguese patientsPublication . Ferreira, F.; Esteves, S.; Almeida, L.S.; Gaspar, A.; da Costa CD, Janeiro P.; Bandeira, A.; Martins, E.S.; Teles, E.L.; Garcia, P.; Azevedo, L.; Vilarinho, L.Trimethylaminuria (TMAu) or "fish odor syndrome" is a metabolic disorder characterized by the inability to convert malodorous dietarily-derived trimethylamine (TMA) to odorless TMA N-oxide by the flavin-containing monooxygenase 3 (FMO3). Affected individuals unable to complete this reaction exude a "fishy" body odor due to the secretion of TMA in their corporal fluids leading to a variety of psychosocial problems. Interindividual variability in the expression of FMO3 gene may affect drug and foreign chemical metabolism in the liver and other tissues. Therefore, it is important to screen for common TMAu mutations but also extend the search to other genetic variants in order to correlate genotype and disease-associated phenotypes. In this study, 25 Portuguese patients with phenotype suggestive of TMAu were evaluated for molecular screening of the FMO3 gene. Herein, we found 16 variants in the FMO3 coding region, some of which had not been previously documented (Gly38Trp, Asp232Val, Thr307Pro, Ser310Leu). Whenever common variants (Glu158Lys, Glu308Gly) were considered in combination a distinct pattern between the control population and patients was observed, mainly in what concerns the presence of Lys158 and Gly308 in homozygous state. Further studies are necessary to clarify the pathogenicity of novel variants identified in this study, as well as the effect of the common single nucleotide polymorphisms, which may play an important role in disease presentation and/or protective mechanism to xenobiotics drugs or environment.