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.
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 del6.2kb 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.
Fyfe
John C
JC
Laboratory of Comparative Medical Genetics, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA. fyfe@cvm.msu.edu
Kurzhals
Rebeccah L
RL
Hawkins
Michelle G
MG
Wang
Ping
P
Yuhki
Naoya
N
Giger
Urs
U
Van Winkle
Thomas J
TJ
Haskins
Mark E
ME
Patterson
Donald F
DF
Henthorn
Paula S
PS
D015061:1,4-alpha-Glucan Branching Enzyme / Q000235:genetics*; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D001947:Breeding; D002415:Cats; D005091:Exons; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006011:Glycogen Storage Disease Type IV / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008099:Liver / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009468:Neuromuscular Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010375:Pedigree
D006003:Glycogen; D015061:1,4-alpha-Glucan Branching Enzyme