title: Mouse model of X-linked Alport syndrome.
abstract: X-linked Alport syndrome (XLAS) is a progressive disorder of basement membranes caused by mutations in the COL4A5 gene, encoding the alpha5 chain of type IV collagen. A mouse model of this disorder was generated by targeting a human nonsense mutation, G5X, to the mouse Col4a5 gene. As predicted for a nonsense mutation, hemizygous mutant male mice are null and heterozygous carrier female mice are mosaic for alpha5(IV) chain expression. Mutant male mice and carrier female mice are viable through reproductive age and fertile. Mutant male mice died spontaneously at 6 to 34 wk of age, and carrier female mice died at 8 to 45 wk of age, manifesting proteinuria, azotemia, and progressive and manifold histologic abnormalities of the kidney glomerulus and tubulointerstitium. Ultrastructural abnormalities of the glomerular basement membrane, including lamellation and splitting, were characteristic of human XLAS. The mouse model described here recapitulates essential clinical and pathologic findings of human XLAS. With alpha5(IV) expression reflecting X-inactivation patterns, it will be especially useful in studying determinants of disease variability in the carrier state.
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Rheault
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Kren
authors.forename: Beth K
authors.initials: BK
authors.lastname: Thielen
authors.forename: Hector A
authors.initials: HA
authors.lastname: Mesa
authors.forename: John T
authors.initials: JT
authors.lastname: Crosson
authors.forename: William
authors.initials: W
authors.lastname: Thomas
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sado
authors.forename: Clifford E
authors.initials: CE
authors.lastname: Kashtan
authors.forename: Yoav
authors.initials: Y
authors.lastname: Segal
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D018389:Codon, Nonsense; D024141:Collagen Type IV / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D009394:Nephritis, Hereditary / Q000235:genetics* / Q000473:pathology*; D009584:Nitrogen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D014960:X Chromosome
chemical_list: C478159:COL4A5 protein, human; D018389:Codon, Nonsense; D024141:Collagen Type IV; D012333:RNA, Messenger; D012260:Ribonucleases; D009584:Nitrogen