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Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia).

Publication ,  Journal Article
Kishnani, PS; Faulkner, E; VanCamp, S; Jackson, M; Brown, T; Boney, A; Koeberl, D; Chen, YT
Published in: Vet Pathol
January 2001

A canine model of glycogen storage disease Ia (GSD Ia), similar clinically, biochemically, and pathologically to the human disease, was established by crossbreeding Maltese and Beagle dogs carrying a mutated, defective glucose-6-phosphatase (G-6-Pase) gene. Ten puppies were born in three litters from these crossbreedings. Six were homozygous for the previously described M121I GSD Ia mutation. Of these six affecteds, two were stillborn, and one died at 2, 32, and 60 days of life, respectively (puppies A, B, C, D, E), while one is alive at age 15 months (puppy F). Affected puppies exhibited tremors, weakness, and neurologic signs when hypoglycemic. They had postnatal growth retardation and progressive hepatomegaly. Biochemical abnormalities included fasting hypoglycemia, hyperlactacidemia, hypercholesterolemia, hypertriglyceridemia, and hyperuricemia. Microscopic examination of tissues from affected puppies showed diffuse, marked hepatocellular vacuolation, with distended clear hepatocytes and central to marginally located rounded nuclei. In the kidneys of puppies D and E, there was segmental glomerular sclerosis and vacuolation of proximal convoluted tubular epithelium. Biochemical analysis revealed increased liver glycogen content and isolated markedly reduced G-6-Pase enzyme activity in liver and kidney. The canine G-6-Pase gene was characterized by screening a canine genomic library. It spans approximately 11.8 kb and consists of five exons with >90% amino acid sequence homology to the derived human sequence. The first 1.5 kb of the 5' region was sequenced and contains several putative response element motifs homologous to the human 5' region. Establishment of this canine colony of GSD Ia that closely resembles human disease and isolation of the canine genomic gene provides an excellent model for studying pathophysiology and long-term complications and an opportunity to develop novel therapeutic approaches such as drug and gene therapy.

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Published In

Vet Pathol

DOI

ISSN

0300-9858

Publication Date

January 2001

Volume

38

Issue

1

Start / End Page

83 / 91

Location

United States

Related Subject Headings

  • Veterinary Sciences
  • Sequence Analysis, DNA
  • Point Mutation
  • Molecular Sequence Data
  • Microscopy, Electron
  • Male
  • Liver Glycogen
  • Liver
  • Kidney
  • Humans
 

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Kishnani, P. S., Faulkner, E., VanCamp, S., Jackson, M., Brown, T., Boney, A., … Chen, Y. T. (2001). Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia). Vet Pathol, 38(1), 83–91. https://doi.org/10.1354/vp.38-1-83
Kishnani, P. S., E. Faulkner, S. VanCamp, M. Jackson, T. Brown, A. Boney, D. Koeberl, and Y. T. Chen. “Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia).Vet Pathol 38, no. 1 (January 2001): 83–91. https://doi.org/10.1354/vp.38-1-83.
Kishnani PS, Faulkner E, VanCamp S, Jackson M, Brown T, Boney A, et al. Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia). Vet Pathol. 2001 Jan;38(1):83–91.
Kishnani, P. S., et al. “Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia).Vet Pathol, vol. 38, no. 1, Jan. 2001, pp. 83–91. Pubmed, doi:10.1354/vp.38-1-83.
Kishnani PS, Faulkner E, VanCamp S, Jackson M, Brown T, Boney A, Koeberl D, Chen YT. Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia). Vet Pathol. 2001 Jan;38(1):83–91.
Journal cover image

Published In

Vet Pathol

DOI

ISSN

0300-9858

Publication Date

January 2001

Volume

38

Issue

1

Start / End Page

83 / 91

Location

United States

Related Subject Headings

  • Veterinary Sciences
  • Sequence Analysis, DNA
  • Point Mutation
  • Molecular Sequence Data
  • Microscopy, Electron
  • Male
  • Liver Glycogen
  • Liver
  • Kidney
  • Humans