The African Origin of the Common Mutation in African American Patients with Glycogen-Storage Disease Type II (original) (raw)
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American journal of human genetics, 1989
The molecular nature of lysosomal alpha-glucosidase deficiency was studied in five South African families with glycogenosis type II. Distinct ethnic origins were represented. Two new mutant acid alpha-glucosidase alleles were discovered. In two infantile patients from a consanguineous Indian family we found for the first time an acid alpha-glucosidase precursor of reduced size. The mutant precursor appeared normally glycosylated and phosphorylated but was not processed to mature enzyme. Abnormalities of the mRNA were not obvious, but digestion of genomic DNA with HindIII, BglII, and StuI revealed for each enzyme a fragment of increased length. Heterozygosity was demonstrated in the parents. Complete lack of acid alpha-glucosidase mRNA, as well as deficiency of precursor synthesis, was observed in two black baby girls from unrelated families. In these cases the length of all restriction-enzyme fragments was normal. Reduced enzyme synthesis but normal processing was registered in juve...
The American Journal of Human Genetics
The molecular nature of lysosomal a-glucosidase deficiency was studied in five South African families with glycogenosis type II. Distinct ethnic origins were represented. Two new mutant acid a-glucosidase alleles were discovered. In two infantile patients from a consanguineous Indian family we found for the first time an acid a-glucosidase precursor of reduced size. The mutant precursor appeared normally glycosylated and phosphorylated but was not processed to mature enzyme. Abnormalities of the mRNA were not obvious, but digestion of genomic DNA with HindIII, BgfII, and StuI revealed for each enzyme a fragment of increased length. Heterozygosity was demonstrated in the parents. Complete lack of acid a-glucosidase mRNA, as well as deficiency of precursor synthesis, was observed in two black baby girls from unrelated families. In these cases the length of all restriction-enzyme fragments was normal. Reduced enzyme synthesis but normal processing was registered in juvenile and young adult Cape colored patients. The extensive heterogeneity of glycogenosis type II is emphasized in these studies on various ethnic groups. The newly discovered mutants are valuable for the understanding of clinical diversity as a result of allelic variation.
Mutation frequencies for glycogen storage disease Ia in the Ashkenazi Jewish population
American Journal of Medical Genetics, 2004
Glycogen storage disease type Ia (GSDIa) is a severe autosomal recessive disorder caused by deficiency of the enzyme D-glucose-6-phosphatase (G6Pase). While numerous mutations have been found in cosmopolitan European populations, Ashkenazi Jewish (AJ) patients appear to primarily carry the R83C mutation, but possibly also the Q347X mutation found generally in Caucasians.
Molecular Biology Reports, 2014
Pompe disease or glycogen storage disease type II is a glycogen storage disorder associated with malfunction of the acid a-glucosidase enzyme (GAA; EC.3.2.1.3) leading to intracellular aggregations of glycogenin muscles. The infantile-onset type is the most life-threatening form of this disease, in which most of patients suffer from cardiomyopathy and hypotonia in early infancy. In this study, a typical case of Pompe disease was reported in an Iranian patient using molecular analysis of the GAA gene. Our results revealed a new c.1824_1828dupATACG mutation in exon 13 of the GAA gene. In conclusion, with the finding of this novel mutation, the genotypic spectrum of Iranian patients with Pompe disease has been extended, facilitating the definition of disease-related mutations. Keywords Infantile-onset Pompe disease Á Glycogen storage disease type II Á c.1824_1828dupATACG Á Acid a-glucosidase gene
A pseudodeficiency allele (D152N) of the human beta-glucuronidase gene
The American Journal of Human Genetics, 1995
We present evidence that a 48OG--A transition in the coding region of the j-glucuronidase gene, which results in an aspartic-acid-to-asparagine substitution at amino acid position 152 (D152N), produces a pseudodeficiency allele (GUSBp) that leads to greatly reduced levels of P-glucuronidase activity without apparent deleterious consequences. The 48OG-+A mutation was found initially in the pseudodeficient mother of a child with mucopolysaccharidosis VII (MPSVII), but it was not on her disease-causing allele, which carried the L176F mutation. The 480G-+A change was also present in an unrelated individual with another MPSVII allele who had unusually low 0-glucuronidase activity, but whose clinical symptoms were probably unrelated to P-glucuronidase deficiency. This individual also had an R357X mutation, probably on his second allele. We screened 100 unrelated normal individuals for the 48OG-+A mutation with a PCR method and detected one carrier. Reduced P-glucuronidase activity following transfection of COS cells with the D152N cDNA supported the causal relationship between the D152N allele and pseudodeficiency. The mutation reduced the fraction of expressed enzyme that was secreted. Pulse-chase experiments indicated that the reduced activity in COS cells was due to accelerated intracellular turnover of the D152N enzyme. They also suggested that a potential glycosylation site created by the mutation is utilized in -50% of the enzyme expressed.
Neuromuscular Disorders, 2002
Glycogen storage disease type II is an autosomal recessive muscle disorder due to deficiency of lysosomal acid a-glucosidase and the resulting intralysosomal accumulation of glycogen. We found six novel mutations in three Spanish classic infantile onset glycogen storage disease type II patients with involvement of both cardiac and skeletal muscle; three missense mutations (G219R, E262K, M408V), a nonsense mutation (Y191X), a donor splice site mutation (IVS18 12gt. ga) and an in frame deletion of an asparagine residue (nt1408-1410). The missense mutations were not found in 100 normal chromosomes and therefore are not normal polymorphic variants. The splice site mutation was subsequently detected in an additional 'Spanish' infantile onset glycogen storage disease type II patient from El Salvador. Further studies will be required to determine if the IVS18 12gt. ga splice site mutation might in fact be a relatively common Spanish mutation. Mutations among Spanish glycogen storage disease type II patients appear to be genetically heterogeneous and differ from common mutations in neighboring countries.