STOCK Crb1^rd8/J

Stock number: 003392
Research areas: Cell Biology Research, Developmental Biology Research, Mouse/Human Gene Homologs, Neurobiology Research, Sensorineural Research

Description

Retinal degeneration 8 (rd8) is a spontaneous frame shift mutation in the Crb1 (crumbs homolog 1 (Drosophila)) gene. Mice homozygous for the rd8 allele exhibit a discontinuous and fragmented zona adherens, shortened photoreceptor inner and outer segments, and areas of retinal degeneration (retinal spotting).

Detailed description

Crb1 (crumbs homolog 1 (Drosophila)) encodes a transmembrane protein that localizes to the apical membrane of epithelial cells and is involved cell polarity in the retina and in the assembly of zonula adherens. Mutations in CRB1 are associated with retinitis pigmentosa and Lebers congenital amaurosis. Mice homozygous for retinal degeneration 8 (rd8) exhibit a discontinuous and fragmented zona adherens, shortened photoreceptor inner and outer segments by 2 weeks of age, and large retinal spots. In contrast to phenotypes associated with other retinal degeneration alleles, retinal degeneration in rd8 mutants is localized to the retinal spots. Within these spots, caused by retinal folds and pseudorosettes, retinal thinning in both the inner and outer nuclear layers is observed. The phenotype associated with rd8 allele is variable depending on genetic background. On the C57BL/6 background, 19% of homozygotes do not exhibit retinal spotting.

Development

Although all C3H strains carry the retinal degeneration 1 mutation of Pde6b, retinas of C3fBAnl.Cg-Cat^b/AnlJ mice were found to have a peculiar, granular appearance distinct from the usual retinal degeneration 1 phenotype. F2 progeny of a cross of C3fBAnl.Cg-Cat^b/AnlJ and C57BL/6ByJ mice exhibited three retinal phenotypes: 1) normal; 2) patches of pigment deposition and large, diffuse pigmented regions typical of retinal degeneration 1 homozygotes; and 3) small, discrete, light-colored dots throughout the fundus. Mice exhibiting the last phenotype were intercrossed among themselves to produce a stock that was homozygous for Mfrp^rd6 and for the wild-type allele of Pde6b. During this process, a separate mutation with a distinct map position was identified and characterized as Crb1^rd8. STOCK Crb1^rd8 Mfrp^rd6/J was homozygous for both Mfrp^rd6 and Crb1^rd8 on this mixed genetic background that derived in part from C57BL/6ByJ, C3H, 101, and a linkage testing stock derived from non-inbred stocks. In order to isolate Crb1^rd8 this stock was backcrossed to C57BL/6ByJ once more, the offspring intercrossed, and their offspring were selected for the Crb1^rd8 phenotype. This mutation was then backcrossed to C57BL/6J for 4 generations before this strain was maintained by sibling intercrossing.

Allele

Symbol: Crb1^rd8
Name: retinal degeneration 8
MGI accession ID: MGI:2676366
Generation method: Spontaneous
Synonyms: Crb1^6N; nmf144; Rd8^-
Marker symbol: Crb1
Marker name: crumbs family member 1, photoreceptor morphogenesis associated
Marker synonyms: 7530426H14Rik; A930008G09Rik; CRB1-A; CRB1-B; CRB1-C; LCA8; RP12
Chromosome: 1
Strain of origin: C57BL/6By or C57BL/6N
Molecular note: The mutation in the rd8 mouse has been identified as a single base deletion of a C (G on forward strand) at coding nucleotide 3481 in the gene. This deletion causes a frame shift and a premature stop codon that truncates the transmembrane and cytoplasmic domain of the protein after amino acid 1207. This mutation has been found to be present in all sublines of C57BL/6N and in C57BL/6ByJ, but not in any C57BL/6J subline. It occurred sometime between transfer of mice from JAX to NIH, in 1951, and from NIH to Donald Bailey, in 1961.

Allele

Symbol: Cdh23^ahl
Name: age related hearing loss 1
MGI accession ID: MGI:3028349
Generation method: Spontaneous
Synonyms: Cdh23^753A; mdfw
Marker symbol: Cdh23
Marker name: cadherin 23 (otocadherin)
Marker synonyms: 4930542A03Rik; ahl; bob; CDHR23; mdfw; nmf112; nmf181; nmf252; PITA5; sals; USH1D
Chromosome: 10
Strain of origin: multiple strains
Molecular note: Genetic complementation tests have shown allelism between the mdfw (modifier of deaf waddler) locus and the ahl locus. Further analysis has shown this is caused by a G-to-A transition at coding nucleotide position 753 of Cdh23 (SNP rs257098870) at the 3' end of exon 7 (in ENSMUST00000073242). This hypomorphic allele changes splice donor site G-GT to A-GT, causing skipping of out-of-frame exon 7. This is predicted to delete part of the 2nd and 3rd ectodomains in the encoded peptide and cause reduced message stability. Twenty-seven strains classified with ahl and carrying the 753A allele include: CD-1, RBF/DnJ, PL/J, AKR/J, RF/J, BALB/cBy, A/WySnJ, P/J, SENCARA/PtJ, DBA/1J, ALS/LtJ, C58/J, C57BLKS/J, 129P1/ReJ, C57BR/cd, SKH2/J, BUB/Bn, MA/MyJ, LP/J, 129X1/SvJ, NOR/LtJ, A/J, C57BL/6, NOD/LtJ, DBA/2J, ALR/LtJ, C57L/J. Strains classified with ahl that DO NOT carry this mutation include: 129S1/SvImJ, C3H/HeSnJ, I/LnJ, YBR/Ei, MRL/MpJ.