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Genetic cause of X-linked Alport syndrome in a family of domestic dogs

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Abstract

Alport syndrome is a hereditary disease of type IV (basement membrane) collagens that occurs spontaneously in humans and dogs. In the human, X-linked Alport syndrome (XLAS) is caused by mutations in COL4A5, resulting in absence of type IV collagen α5 chains from the glomerular basement membrane (GBM) of affected individuals. The consequence of this defect is progressive renal failure, for which the only available treatments are dialysis and transplantation. Recent studies support the prospect of gene transfer therapy for Alport syndrome, but further development of required technologies and demonstration of safety and efficacy must be accomplished in a suitable animal model. We previously identified and have propagated a family of mixed-breed dogs with an inherited nephropathy that exhibits the clinical, immunohistochemical, pathological, and ultrastructural features of human XLAS. To identify the causative mutation, COL4A5 cDNAs from normal and affected dogs were sequenced in their entirety. Sequence analyses revealed a 10-bp deletion in exon 9 of affected dogs. This deletion causes a frame-shift that results in a premature stop codon in exon 10. Characterization of the causative mutation was followed by development of an allele-specific test for identification of dogs in this kindred that are destined to develop XLAS.

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Author information

Authors and Affiliations

  1. Department of Pathobiology, College of Veterinary Medicine, Texas A&M University, 77843-4467, College Station, TX, USA

    Melissa L. Cox & Keith E. Murphy

  2. Program in Genetics, Texas A&M University, 77843, College Station, Texas, USA

    Melissa L. Cox & Keith E. Murphy

  3. Department of Small Animal Medicine and Surgery, Texas A&M University, 77843, College Station, Texas, USA

    George E. Lees

  4. Department of Pediatrics, University of Minnesota Medical School, 55455, Minneapolis, Minnesota, USA

    Clifford E. Kashtan

Authors
  1. Melissa L. Cox
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  2. George E. Lees
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  3. Clifford E. Kashtan
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  4. Keith E. Murphy
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Corresponding author

Correspondence to Keith E. Murphy.

Additional information

The sequence determined during the course of this work has been deposited in GenBank. The Accession number is AF470624.

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Cox, M.L., Lees, G.E., Kashtan, C.E. et al. Genetic cause of X-linked Alport syndrome in a family of domestic dogs. Mammalian Genome 14, 396–403 (2003). https://doi.org/10.1007/s00335-002-2253-9

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  • DOI: https://doi.org/10.1007/s00335-002-2253-9

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