title: Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis.
abstract: Cone-rod dystrophy 1 (cord1) is a recessive condition that occurs naturally in miniature longhaired dachshunds (MLHDs). We mapped the cord1 locus to a region of canine chromosome CFA15 that is syntenic with a region of human chromosome 14 (HSA14q11.2) containing the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) gene. Mutations in RPGRIP1 have been shown to cause Leber congenital amaurosis, a group of retinal dystrophies that represent the most common genetic causes of congenital visual impairment in infants and children. Using the newly available canine genome sequence we sequenced RPGRIP1 in affected and carrier MLHDs and identified a 44-nucleotide insertion in exon 2 that alters the reading frame and introduces a premature stop codon. All affected and carrier dogs within an extended inbred pedigree were homozygous and heterozygous, respectively, for the mutation. We conclude the mutation is responsible for cord1 and demonstrate that this canine disease is a valuable model for exploring disease mechanisms and potential therapies for human Leber congenital amaurosis.
authors.affiliation: Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk CB8 7UU, UK. cathryn.mellersh@aht.org.uk
authors.forename: C S
authors.initials: CS
authors.lastname: Mellersh
authors.forename: M E G
authors.initials: ME
authors.lastname: Boursnell
authors.forename: L
authors.initials: L
authors.lastname: Pettitt
authors.forename: E J
authors.initials: EJ
authors.lastname: Ryder
authors.forename: N G
authors.initials: NG
authors.lastname: Holmes
authors.forename: D
authors.initials: D
authors.lastname: Grafham
authors.forename: O P
authors.initials: OP
authors.lastname: Forman
authors.forename: J
authors.initials: J
authors.lastname: Sampson
authors.forename: K C
authors.initials: KC
authors.lastname: Barnett
authors.forename: S
authors.initials: S
authors.lastname: Blanton
authors.forename: M M
authors.initials: MM
authors.lastname: Binns
authors.forename: M
authors.initials: M
authors.lastname: Vaudin
mesh_terms: D000818:Animals; D002648:Child; D002675:Child, Preschool; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004285:Dogs; D005091:Exons / Q000235:genetics; D006801:Humans; D007223:Infant; D016254:Mutagenesis, Insertional; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D010375:Pedigree; D011506:Proteins / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D011506:Proteins; C415903:RPGRIP1 protein, human