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

https://doi.org/10.1016/j.ymgme.2006.12.003Get rights and content

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.

Section snippets

Animals

We established a feline GSD IV breeding colony by mating a carrier male NFC (cat A in Fig. 1) to an unrelated female domestic shorthair cat (cat B in Fig. 1). Matings were performed by placing females housed under 16 h of light/day in a room occupied by a specific male until pregnancy could be detected by abdominal palpation. Deliveries generally occurred unobserved and unaided during nighttime hours. We performed all matings, specimen collection, determination of clinical phenotype, and

Breeding experiments

We identified a purebred NFC male as a carrier of GSD IV by measurement of approximately half-normal GBE activity in peripheral blood leukocytes and liver (cat A in Fig. 1). A breeding colony was established by mating this cat with an unrelated healthy domestic shorthair cat of known lineage (cat B in Fig. 1). GBE activity was measured in leukocytes of offspring from 4 litters produced by this mating, and females considered to have half-normal activity were raised for matings with the

Discussion

In humans, the age of onset, organ distribution, and clinical course of GSD IV is highly variable, ranging from mild nonprogressive hepatopathy to fetal neuromuscular dysfunction and immediate-postnatal cardiopulmonary collapse [4]. This clinical heterogeneity has been attributed to differing GBE1 mutations that, in turn, are presumed to provide varied amounts of residual enzyme activity, albeit the available assays for GBE activity measurement are imprecise at lower activities and vary between

Acknowledgments

This work was supported by the NIH Referral Center—Animal Models of Human Genetic Disease (RR02512) at the University of Pennsylvania School of Veterinary Medicine and the Genetics Research Fund of the Michigan State University College of Veterinary Medicine. We thank Adam Seng and Polly Foureman, DVM, for DNA testing of privately owned cats, and Barry Prior, currently of the Department of Veterinary Biomedical Sciences, University of Missouri, Columbia, for the muscle nuclear magnetic

References (42)

  • Y.-T. Chen

    Glycogen storage diseases

  • D.H. Andersen

    Familial cirrhosis of the liver with storage of abnormal glycogen

    Lab. Invest.

    (1956)
  • B.I. Brown et al.

    Lack of an alpha-1,4-glucan: alpha-1,4-glucan 6-glycosyl transferase in a case of type IV glycogenosis

    Proc. Natl. Acad. Sci. USA

    (1966)
  • S.W. Moses et al.

    The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies

    Curr. Mol. Med.

    (2002)
  • Y. Bao et al.

    Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene

    J. Clin. Invest.

    (1996)
  • C. Bruno et al.

    Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV)

    Neurology

    (2004)
  • J.A. Render et al.

    Amylopectinosis in fetal and neonatal quarter horses

    Vet. Pathol.

    (1999)
  • S.J. Valberg et al.

    Glycogen branching enzyme deficiency in quarter horse foals

    J. Vet. Intern. Med.

    (2001)
  • T.L. Ward et al.

    Glycogen branching enzyme (GBE1) mutation causing equine glycogen storage disease IV

    Mamm. Genome

    (2004)
  • J.C. Fyfe et al.

    Glycogen storage disease type IV: inherited deficiency of branching enzyme activity in cats

    Pediatr. Res.

    (1992)
  • J.R. Coates et al.

    A case presentation and discussion of type IV glycogen storage disease in a Norwegian forest cat

    Prog. Vet. Neurol.

    (1996)
  • Cited by (25)

    • Disorders of Carbohydrate Metabolism

      2020, Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Metabolic Disorders
    • Treatment of pregnant spiny mice at mid gestation with a synthetic glucocorticoid has sex-dependent effects on placental glycogen stores

      2013, Placenta
      Citation Excerpt :

      These findings lead us to consider if fetal sex and/or DEX administration affects the deposition of glycogen in the placenta. We hypothesise that glycogen deposition will display both a constitutive and glucocorticoid-induced sex-dependent expression within the placenta, and these differences will be driven by differential expression of genes known to be involved in the synthesis (e.g., glycogen synthase 1 (muscle) [GYS1] [19]; glucan (1,4-alpha-), branching enzyme 1 [GBE1] [20]; UDP-glucose pyrophosphorylase 2 [UGP2] [19]) and degradation (e.g., forkhead box O1 [FOXO1] [21]; glycogen synthase kinase 3 beta [GSK3B] [21]; phosphorylase, glycogen, liver [PYGL] [22]) of glycogen within the placenta. To investigate this hypothesis we used the spiny mouse (Acomys cahirinus), a rodent species with a discoid haemotrichorial placenta [23].

    • Disorders of Carbohydrate Metabolism

      2013, Emery and Rimoin's Principles and Practice of Medical Genetics
    View all citing articles on Scopus
    1

    Present address: Department of Biology, University of Utah, Salt Lake City, UT 84112, USA.

    2

    Present address: Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.

    View full text