129S1.B6-(rs3696307-rs257098870)/Kjn

Stock number: 018926
Research areas: Neurobiology Research, Sensorineural Research

Description

The C57BL/6J-derived congenic interval in this strain includes the recessive Cdh23^ahl allele and the dominant Mahl^C57BL/6J QTL from C57BL/6J backcrossed onto 129S1/SvImJ and bred to homozygosity. This results in the age related hearing loss phenotype on a predominantly 129S1/SvImJ background.

Detailed description

The C57BL/6J-derived congenic interval in this strain includes the recessive Cdh23^ahl allele and the dominant Mahl^C57BL/6J QTL from C57BL/6J backcrossed onto 129S1/SvImJ and bred to homozygosity. This results in the age related hearing loss phenotype on a predominantly 129S1/SvImJ background. RT-PCR transcripts of cochlear extracts from six-week-old homozygotes showed exon skipping, and wild-type Cdh23 transcripts in this strain were approximately 24% of total Cdh23 transcripts. The Mahl^C57BL/6J QTL ameliorates the hair cell loss and hearing deficit so that progression of hearing loss is less severe than that caused by the c.753A single nucleotide variant, which is equivalent to the Cdh23^ahl molecular lesion, on the 129S background (Stock No. 016208). Relative to that single nucleotide variant homozygous for the Mahl^129S1/SvImJ allele, this congenic has lower ABR thresholds at 8 and 16 kHz up to 9 months of age, and 32 kHz up to 6 months of age. Inner and outer cochlear hair cell loss at 9 months of age is more severe than in 129S1/SvImJ controls, but less severe than in 6 month old c.753A point mutants on the 129S background.

Development

A segment of Chromosome 10 containing the Cdh23^ahl allele was backcrossed from C57BL/6J onto 129S1/SvImJ for 10 generations and then sibling intercrossed to homozygosity. The proximal breakpoint of the fixed congenic interval is between rs3661754 and rs3696307 and the distal breakpoint is between rs257098870 and rs29330969.

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.

Allele

Symbol: Mahl^C57BL/6J
Name: C57BL/6J
MGI accession ID: MGI:5898294
Generation method: QTL
Marker symbol: Mahl
Marker name: modifier of age related hearing loss
Chromosome: 10
Strain of origin: C57BL/6J
Molecular note: In the heterozygous or homozygous state this allele confers some amelioration of the hair cell loss and hearing loss caused by the age related hearing loss mutation on the 129S1 background