Canine RPGRIP1 mutation establishes cone–rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis

Mellersh, Cathryn S.; Boursnell, M. E. G.; Pettitt, Louise; Ryder, Edward; Holmes, Nigel G.; Grafham, Darren; Forman, Oliver P.; Sampson, Jeffrey R.; Barnett, K. C.; Blanton, Susan H.; Binns, M. M.; Vaudin, Mark D.

doi:10.1016/j.ygeno.2006.05.004

Cited by 94 publications

(117 citation statements)

References 46 publications

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“…The cord1 locus was mapped to a region of canine chromosome 15 containing the RPGRIP1 gene. Genome sequencing identified a 44-nucleotide insertion in exon 2 of RPGRIP1 that alters the reading frame and introduces a premature stop codon (Mellersh et al 2006). In the initial study that identified the RPGRIP1 mutation, affected and carrier dogs within an extended inbred pedigree were homozygous and heterozygous, respectively, for the mutation (Mellersh et al 2006).…”

Section: Animal Modelsmentioning

confidence: 99%

Leber Congenital Amaurosis Caused by Mutations in RPGRIP1

2014

Cold Spring Harbor Perspectives in Medicine

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Recessive null mutations in retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1) gene are the cause of LCA6 and account for 5% to 6% of the total patient population. RPGRIP1 has an essential role in the photoreceptor connecting cilia, and photoreceptors lacking RPGRIP1 are unable to maintain the light sensing outer segments. As a result, patients lose retinal functions at an early age but retain photoreceptors in the central retina well into adulthood thus holding out the prospect for gene augmentation therapies. Laboratory studies in animal models have demonstrated efficacy of gene therapy in slowing disease progression. With further refinement in the design of the replacement gene construct, clinical trials for Leber congenital amaurosis (LCA) caused by RPGRIP1 mutations could be in the offing in the near future.

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Section: Animal Modelsmentioning

confidence: 99%

Leber Congenital Amaurosis Caused by Mutations in RPGRIP1

2014

Cold Spring Harbor Perspectives in Medicine

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“…At 52 wk, most affected animals still had recordable electroretinography (ERG) responses. In the MLHDs, the ERG responses were nonrecordable already at the age of 40 wk (Mellersh et al 2006).…”

Section: Discussionmentioning

confidence: 91%

“…Mutations in RPGRIP1, however, have been reported to be a cause of LCA (Dryja et al 2001;Gerber et al 2001), while mutations causing residual RPGRIP1 activity may lead to phenotypes such as RP or crd, which are less severe than LCA (Cremers et al 2002). Some RPGRIP1 gene mutations are also associated with recessive crd in human (Hameed et al 2003) and dog (Mellersh et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…The standard wire-haired dachshund (SWHD), the miniature long-haired dachshund (MLHD), and the pit bull terrier (PBT) are the only dog breeds to date known to be affected by crd (Kijas et al 2004;Mellersh et al 2006;Ropstad et al 2007a). A mutation in canine RPGRIP1 has been demonstrated to cause autosomal recessive crd in MLHDs (Mellersh et al 2006), while the genetic basis of the crd found in the PBT is still unknown (Kijas et al 2004).…”

mentioning

confidence: 99%

“…A mutation in canine RPGRIP1 has been demonstrated to cause autosomal recessive crd in MLHDs (Mellersh et al 2006), while the genetic basis of the crd found in the PBT is still unknown (Kijas et al 2004).…”

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confidence: 99%

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A deletion in nephronophthisis 4 (NPHP4) is associated with recessive cone-rod dystrophy in standard wire-haired dachshund

Wiik¹,

Wade²,

Biagi³

et al. 2008

Genome Res.

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Cone-rod dystrophy is a retinal degenerative disorder occurring naturally in man and dog. Here we identify a novel gene for early-onset cone-rod dystrophy in the wire-haired dachshund. For the first time, we use genome-wide association-based Sibling Transmission Disequilibrium Test (sibTDT) analysis of only 13 discordant sib-pairs to identify a single significantly associated 6.5-Mb region (PrawTDT = 4.8 × 10−5, PgenomeTDT = 6 × 10−4) on canine chromosome 5, containing more than 70 genes. Segregation studies using microsatellites in the candidate region including additional meiosis supported the sibTDT analysis but could not further reduce the area. Candidate gene resequencing identified a 180-bp deletion in exon/intron 5 of NPHP4 (nephronophthisis 4, also known as nephroretinin). RT-PCR analysis of NPHP4 in cases and controls showed exon skipping of exon 5, resulting in a truncated protein that retains the binding domain interacting with nephronophthisis 1 (also known as nephrocystin-1) in the kidney but lacks the domain interacting with RPGRIP1 in retina. We suggest that this deletion in the canine NPHP4 gene is the cause of cone-rod dystrophy in the standard wire-haired dachshund. In humans, mutations in NPHP4 have been associated with simultaneous eye and kidney disease. Here we describe the first naturally occurring mutation in NPHP4 without additional kidney disease. Further studies will permit elucidation of the complex molecular mechanism of this retinopathy and the development of potential therapies.

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Histologic manifestations of retinal disease

2018

Histologic Basis of Ocular Disease in Animals

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Canine RPGRIP1 mutation establishes cone–rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis

Cited by 94 publications

References 46 publications

Leber Congenital Amaurosis Caused by Mutations in RPGRIP1

Leber Congenital Amaurosis Caused by Mutations in RPGRIP1

A deletion in nephronophthisis 4 (NPHP4) is associated with recessive cone-rod dystrophy in standard wire-haired dachshund

Histologic manifestations of retinal disease

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