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Available from: Elizabeth M Adams, Aug 24, 2015
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    • "A very well documented example of an African–American mutation is the R854X. This alteration was brought to America by the slave trade (Becker et al., 1998) and was found in only one individual in our study at a frequency of 2.6% among all mutations described. When one of the following pathogenic mutations C647W, c.236_246del or R870X was identified in heterozygosity with the three non-pathogenic variants R199H, H223R, and I780V we could observe the development of Pompe disease. "
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    ABSTRACT: Pompe disease is an autosomal recessive disorder linked to GAA gene that leads to a multi-system intralysosomal accumulation of glycogen. Mutation identification in the GAA gene can be very important for early diagnosis, correlation between genotype-phenotype and therapeutic intervention. For this purpose, peripheral blood from 57 individuals susceptible to Pompe disease was collected and all exons of GAA gene were amplified; the sequences and the mutations were analyzed in silico to predict possible impact on the structure and function of the human protein. In this study, 46 individuals presented 33 alterations in GAA gene sequence, among which five (c.547-67C>G, c.547-39T>G, p.R437H, p.L641V and p.L705P) have not been previously described in the literature. The alterations in the coding region included 15 missense mutations, three nonsense mutations and one deletion. One insertion and other 12 single base changes were found in the non-coding region. The mutation p.G611D was found in homozygosis in a one-year-old child, who presented low levels of GAA activity, hypotonia and hypertrophic cardiomyopathy. Two patients presented the new mutation p.L705P in association with c.-32-13T>G. They had low levels of GAA activity and developed late onset Pompe disease. In our study, we observed alterations in the GAA gene originating from Asians, African-Americans and Caucasians, highlighting the high heterogeneity of Brazilian population. Considering that Pompe disease studies are not very common in Brazil, this study will help to better understand the potential pathogenic role of each change in the GAA gene. Furthermore, a precise and early molecular analysis improves genetic counseling besides allowing for a more efficient treatment in potential candidates. Copyright © 2015. Published by Elsevier B.V.
    Gene 02/2015; 561(1). DOI:10.1016/j.gene.2015.02.023 · 2.08 Impact Factor
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    • "Genomic DNA was extracted from whole blood samples using standard procedures. In all patients, the complete GAA open reading frame (19 exons) was amplified by PCR as previously described (Becker et al. 1998). "
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    ABSTRACT: Pompe disease (PD) is a recessive metabolic disorder characterized by acid α-glucosidase (GAA) deficiency, which results in lysosomal accumulation of glycogen in all tissues, especially in skeletal muscles. PD clinical course is mainly determined by the nature of the GAA mutations. Although ~400 distinct GAA sequence variations have been described, the genotype-phenotype correlation is not always evident.In this study, we describe the first clinical and genetic analysis of Colombian PD patients performed in 11 affected individuals. GAA open reading frame sequencing revealed eight distinct mutations related to PD etiology including two novel missense mutations, c.1106 T > C (p.Leu369Pro) and c.2236 T > C (p.Trp746Arg). In vitro functional studies showed that the structural changes conferred by both mutations did not inhibit the synthesis of the 110 kD GAA precursor form but affected the processing and intracellular transport of GAA. In addition, analysis of previously described variants located at this position (p.Trp746Gly, p.Trp746Cys, p.Trp746Ser, p.Trp746X) revealed new insights in the molecular basis of PD. Notably, we found that p.Trp746Cys mutation, which was previously described as a polymorphism as well as a causal mutation, displayed a mild deleterious effect. Interestingly and by chance, our study argues in favor of a remarkable Afro-American and European ancestry of the Colombian population. Taken together, our report provides valuable information on the PD genotype-phenotype correlation, which is expected to facilitate and improve genetic counseling of affected individuals and their families.
    01/2013; 7:39-48. DOI:10.1007/8904_2012_138
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    ABSTRACT: Die Glykogen-Speicherkrankheit (GSD) ist eine seltene Stoffwechselerkrankung, die in verschiedenen Ausprägungen (Typen) vorkommt. Im ersten Teil der Arbeit wird durch Messung der Enzymaktivität von saurer α-Glukosidase und der Enzymaktivität des Branchingenzyms ein Screening-Test durchgeführt. Im zweiten Teil wird durch Genanalyse als diagnostische Methode die Erklärung der Erkrankung auf molekulargenetischer Ebene erforscht, um den Zusammenhang zwischen dem Geno- und Phenotyp zu verstehen.
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