Association of a citrate synthase missense mutation with age-related hearing loss in A/J mice

作者：Johnson Kenneth R^*; Gagnon Leona H; Longo Guess Chantal; Kane Kelly L

来源：Neurobiology of Aging, 2012, 33(8): 1720-1729.

DOI：10.1016/j.neurobiolaging.2011.05.009

• Mouse
• Genetics
• Inbred strain
• A/J
• Age-related hearing loss
• ahl4
• Citrate synthase
• Oxidative stress
• Mitochondria

We previously mapped a locus (ahl4) on distal Chromosome 10 that contributes to the age-related hearing loss of A/J strain mice. Here, we report on a refined genetic map position for ahl4 and its association with a mutation in the citrate synthase gene (Cs). We mapped ahl4 to the distal-most 7 megabases (Mb) of chromosome 10 by analysis of a new linkage backcross and then further narrowed the interval to 5.5 Mb by analysis of 8 C57BL/6J congenic lines with different A/J-derived segments of chromosome 10. A nucleotide variant in exon 3 of Cs is the only known DNA difference within the ahl4 candidate gene interval that is unique to the A/J strain and that causes a nonsynonymous codon change. Multiple lines of evidence implicate this missense mutation (H55N) as the underlying cause of ahl4-related hearing loss, likely through its effects on mitochondrial adenosine trisphosphate (ATP) and free radical production in cochlear hair cells. The A/J mouse thus provides a new model system for in vivo studies of mitochondrial function and hearing loss.

• 出版日期2012-8