A complex rearrangement in GBE1 causes both perinatal hypoglycemic collapse and late-juvenile-onset neuromuscular degeneration in glycogen storage disease type IV of Norwegian forest cats

John C. Fyfe, Rebeccah L. Kurzhals, Michelle Hawkins, Ping Wang, Naoya Yuhki, Urs Giger, Thomas J. Van Winkle, Mark E. Haskins, Donald F. Patterson, Paula S. Henthorn

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Deficiency of glycogen branching enzyme (GBE) activity causes glycogen storage disease type IV (GSD IV), an autosomal recessive error of metabolism. Abnormal glycogen accumulates in myocytes, hepatocytes, and neurons, causing variably progressive, benign to lethal organ dysfunctions. A naturally occurring orthologue of human GSD IV was described previously in Norwegian forest cats (NFC). Here, we report that while most affected kittens die at or soon after birth, presumably due to hypoglycemia, survivors of the perinatal period appear clinically normal until onset of progressive neuromuscular degeneration at 5 months of age. Molecular investigation of affected cats revealed abnormally spliced GBE1 mRNA products and lack of GBE cross-reactive material in liver and muscle. Affected cats are homozygous for a complex rearrangement of genomic DNA in GBE1, constituted by a 334 bp insertion at the site of a 6.2 kb deletion that extends from intron 11 to intron 12 (g. IVS11+1552_IVS12-1339 del6.2 kb ins334 bp), removing exon 12. An allele-specific, PCR-based test demonstrates that the rearrangement segregates with the disease in the GSD IV kindred and is not found in unrelated normal cats. Screening of 402 privately owned NFC revealed 58 carriers and 4 affected cats. The molecular characterization of feline GSD IV will enhance further studies of GSD IV pathophysiology and development of novel therapies in this unique animal model.

Original languageEnglish (US)
Pages (from-to)383-392
Number of pages10
JournalMolecular Genetics and Metabolism
Volume90
Issue number4
DOIs
StatePublished - Apr 2007
Externally publishedYes

Keywords

  • Branching enzyme
  • Enzymopathy
  • Genomic rearrangement
  • Glycogen storage
  • Glycogenosis
  • Hypoglycemia
  • Neuromuscular degeneration

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Endocrinology, Diabetes and Metabolism

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