title: Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI.
abstract: Glycogen storage disease type VI (GSD6) defines a group of disorders that cause hepatomegaly and hypoglycemia with reduced liver phosphorylase activity. The course of these disorders is generally mild, but definitive diagnosis requires invasive procedures. We analyzed a Mennonite kindred with an autosomal recessive form of GSD6 to determine the molecular defect and develop a non-invasive diagnostic test. Linkage analysis was performed using genetic markers flanking the liver glycogen phosphorylase gene ( PYGL ), which was suspected to be the cause of the disorder on biochemical grounds. Mennonite GSD6 was linked to the PYGL locus with a multipoint LOD score of 4.7. The PYGL gene was analyzed for mutations by sequencing genomic DNA. Sequencing of genomic DNA revealed a splice site abnormality of the intron 13 splice donor. Confirmation of the genomic mutation was performed by sequencing RT-PCR products, which showed heterogeneous PYGL mRNA lacking all or part of exon 13 in affected persons. This study is the first to demonstrate that a mutation in the PYGL gene can cause GSD6. This mutation is estimated to be present on 3% of Mennonite chromosomes and the disease affects 0.1% of that population. Determination of this mutation provides a basis for the development of a simple and non-invasive diagnostic test for the disease and the carrier state in this population and confirms biochemical data showing the importance of this gene in glucose homeostasis.
authors.affiliation: Laboratory of Genetic Disease Research and Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chang
authors.forename: M J
authors.initials: MJ
authors.lastname: Rosenberg
authors.forename: H
authors.initials: H
authors.lastname: Morton
authors.forename: C A
authors.initials: CA
authors.lastname: Francomano
authors.forename: L G
authors.initials: LG
authors.lastname: Biesecker
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D006580:Genetic Carrier Screening; D008040:Genetic Linkage; D006013:Glycogen Storage Disease Type VI / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D007223:Infant; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D006005:Phosphorylases / Q000235:genetics*
chemical_list: D008112:Liver Glycogen; D006005:Phosphorylases