Mapping Data

Experiment

• Experiment
  TEXT
• Chromosome
  10
• Reference
  J:139222 Zheng QY, et al., A locus on distal chromosome 10 (ahl4) affecting age-related hearing loss in A/J mice. Neurobiol Aging. 2009 Oct;30(10):1693-705
• ID
  MGI:3815574

Genes

Gene	Assay Type
Cs	visible phenotype
D10Mit35a	PCR amplified length variant
D10Mit205	PCR amplified length variant
D10Mit103	PCR amplified length variant
Cdh23	reported elsewhere

Notes

• Experiment
  Linkage analysis was performed using 27 AXB and BXA (A=A/J; B=C57BL/6J) recombinant inbred strains to identify genetic loci associated with age-related hearing loss. Over 700 loci are included in the AXB/BXA RI strain distribution pattern which was used for linkage analysis. At least 8 animals from each RI strain were evaluated at 6-9 months of age for auditory brainstem response (ABR). Parental strain A/J develops progressive hearing loss immediately after weaning. By 3 months of age A/J animals displayABR thresholds greater than 50 dB while C57BL/6J animals display normal hearing at 6 months of age. Both A/J and C57BL/6J carry the Cdh23^ahl allele on chromosome 10 which predisposes to hearing loss.
  
  Significant linkage to 16 kHz ABR thresholds mapped to distal mouse Chromosome 10 at 69 cM near D10Mit35a (LOD=3.8) and D10Mit205 (LOD=4.3). This locus is distinct from Chd23^ahl (30.3 cM) and is named ahl4 (age related hearing loss 4).
  
  Chromosome substitution strains (CSS) carrying A/J-derived chromosomes on a C57BL/6J genetic background were also evaluated for linkage to hearing loss. At least 8 animals from each CSS were tested for ABR thresholds at 5-7 months of age. The chromosome 10 CSS (C57BL/6J-Chr10^A/J) displayed association to hearing loss thus confirming the presence of ahl4. C57BL/6J-Chr10^A/J animals display earlier onset and more rapid progression of hearing loss as well as elevated 16 kHz ABR thresholds compared to C57BL/6J animals.
  
  Suggestive association to hearing loss and CSS line C57BL/6J-Chr11^A/J was observed suggesting a minor ahl locus may be present on mouse Chromosome 11.
  
  A backcross population of (A/J x CAST/EiJ)F1 x A/J animals was used to confirm ahl4. Linkage to hearing loss at 3 months of age (LOD=8.3) and 6 months of age (LOD=6.4) mapped to 70 cM (125.1 Mb) near D10Mit103. This locus spans 120 Mb - 130 Mb and coincides with ahl4. Cdh23 was also evaluate in the backcross. Animals homozygous for A/J-derived alleles at Cdh23 displayed significantly elevated ABR thresholds at 16 kHz and this locus explained 50% of the trait variance.
  
  Cdh23^ahl at 30.3 cM and ahl4 at 69 cM appear to have additive effects. Backcross animals homozygous for A/J-derived alleles at both Cdh23^ahl and ahl4 display increased 16 kHz ABR thresholds compared to animals homozygous for A/J-derived alleles at Cdh23^ahl and heterozygous for A/J- and CAST/EiJ-derived alleles at ahl4.
  
  The ahl4 interval containsover 100 genes. Myo1a at 70 cM was considered as a candidate gene since mutations inthe humans ortholog are associated with progressive nonsyndromic deafness disorder DFNA48. However,Myo1a knockout mice do not display hearing loss and 7 SNP polymorphisms identified between A/J and C57BL/6J do not lead to amino acid changes or spice sitealterations.