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  • 1
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract We have identified mutations in the phosphorylase kinase (Phk) β subunit gene in a male patient with liver glycogenosis caused by Phk deficiency. The patient’s DNA has been analyzed for mutations in the genes encoding the αL, β, and γTL subunits of Phk, all of which can be responsible for liver glycogenosis, by a strategy primarily based on reverse transcription/polymerase chain reaction of blood RNA and complemented by analysis of genomic DNA. His αL and γTL coding sequences are normal, whereas he is compound-heterozygous for two mutations in the β subunit gene, PHKB. The first is a splice-site mutation (IVS4 [–2A→G]) causing the reading-frame-disrupting deletion of exon 5 in the mRNA from this allele. The second is an Ala117Pro missense mutation, also in exon 5. This is the first missense mutation identified in PHKB, as opposed to nine translation-terminating mutations described to date. It offers an explanation for the unique biochemical phenotype of this patient. In his leukocytes, low Phk activity is measured when tested with the endogenous liver isoform of phosphorylase as the protein substrate, but normal activity is observed when tested with muscle phosphorylase added in vitro. In contrast, Phk activity in his erythrocytes is low with both substrates. The missense mutation may selectively impair the interaction of Phk with one isoform of its substrate protein and may destabilize the enzyme in a cell-type-specific way. This phenotype shares some aspects with X-linked liver glycogenosis subtype 2 (XLG2), a variant of liver Phk deficiency arising from missense mutations in the αL subunit gene (PHKA2), but differs from XLG2 in other respects. The present case demonstrates that mutations in Phk genes other than PHKA2 can also be associated with untypically high activity in certain blood cell types. Moreover, it emphasizes that missense mutations in Phk may cause unusual patterns of tissue involvement that would not be predicted a priori from the tissue specificity of expression of the mutated gene sequences.
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  • 2
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract X-linked liver glycogenosis (XLG) resulting from phosphorylase kinase (Phk) deficiency is one of the most common forms of glycogen storage disease. It is caused by mutations in the gene encoding the liver isoform of the Phk α subunit (PHKA2). In the present study, we address the issue of phenotypic and allelic heterogeneity in XLG. We have identified mutations in seven male patients. One of these patients represents the variant biochemical phenotype, XLG subtype 2 (XLG2), where Phk activity is low in liver but normal or even elevated in erythrocytes. He carries a K189E missense mutation, which adds to the emerging evidence that XLG2 is associated with missense mutations clustering at a few sites. Two patients display clinical phenotypes unusual for liver Phk deficiency, with dysfunction of the kidneys (proximal renal tubular acidosis) or of the nervous system (seizures, delayed cognitive and speech abilities, peripheral sensory neuropathy), respectively, in addition to liver glycogenosis. In the patient with kidney involvement, we have identified a missense mutation (P399S) and a trinucleotide deletion (2858del3) leading to the replacement of two amino acids by one new residue (N953/L954I), and a missense mutation has also been found in the patient with neurological symptoms (G1207W). These two cases demonstrate that PHKA2 mutations can also be associated with uncommon clinical phenotypes. Finally, in four typical XLG cases, we have identified three truncating mutations (70insT, R352X, 567del22) and an in-frame deletion of eight well-conserved amino acids (2452del24). Together, this study adds eight new mutations to the previously known complement of sixteen PHKA2 mutations. All known PHKA2 mutations but one are distinct, indicating pronounced allelic heterogeneity of X-linked liver glycogenosis with mutations in the PHKA2 gene.
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  • 3
    ISSN: 1364-6753
    Keywords: Key words Glycogen storage disease type II ; Mutation analysis ; Phenotypic and allelic heterogeneity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: ABSTRACT Glycogen storage disease type II (GSDII, Pompe's disease) is an autosomal recessive inherited deficiency of lysosomal α-glucosidase (GAA). Clinical as well as biochemical and allelic heterogeneity have been described in GSDII. We identified mutations within the GAA gene in seven unrelated German patients, six with adult- and one with juvenile-onset GSDII. Beside previously described mutations [IVS1 (–13T → G), Δexon 18, C1634T], we characterized four new mutations of GSDII: IVS6 (–22T → G), 271delG, G1912T (Gly638Trp), and 2432insC. The IVS6 (-22T → G) mutation gives rise to aberrant splicing, causing in-frame deletions of 25 or 40 amino acids within the GAA coding sequence and the insertion of a sequence of seven missense amino acids. Two affected siblings and an unrelated patient with adult GSDII are apparently homozygous for the exon 18 deletion. Both siblings are also heteroallelic for IVS1 (–13T → G). In conclusion, we observed pronounced allelic heterogeneity and an unexpectedly high frequency of homozygosity for larger in-frame deletions within the GAA coding sequence in German adult-onset GSDII patients.
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  • 4
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] The αM and αL subunit genes of Phk (PHKA1 and PHKA2) were previously mapped to the X chromosome2,11, and mutations explaining X-linked muscle-specific and X-linked liver-specific Phk deficiency were recently characterized (refs 12–15, and references therein). No mutations have ...
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