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

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...

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Bibliographic Details
Published in:Mammalian genome 2003-06, Vol.14 (6), p.396-403
Main Authors: Cox, Melissa L, Lees, George E, Kashtan, Clifford E, Murphy, Keith E
Format: Article
Language:English
Subjects:
Alport syndrome
Animal models
Animals
Base Sequence
Codon, Nonsense - genetics
Collagen (type IV)
Collagen Type IV - genetics
Dialysis
DNA Primers
Dogs - genetics
Domestic animals
Gene deletion
Gene transfer
Genetic Diseases, X-Linked - veterinary
Genetic Testing
Genetics
Hereditary diseases
Molecular Sequence Data
Mutation
Nephritis, Hereditary - genetics
Nephritis, Hereditary - veterinary
Nephropathy
Nonsense mutation
Renal failure
Sequence Analysis, DNA
Stop codon
Transplantation
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Summary: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.
ISSN:0938-8990
1432-1777
DOI:10.1007/s00335-002-2253-9