title: Association of a citrate synthase missense mutation with age-related hearing loss in A/J mice.
abstract: 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME04609, USA. ken.johnson@jax.org
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Johnson
authors.forename: Leona H
authors.initials: LH
authors.lastname: Gagnon
authors.forename: Chantal
authors.initials: C
authors.lastname: Longo-Guess
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Kane
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D002950:Citrate (si)-Synthase / Q000235:genetics*; D056726:Genetic Association Studies; D008040:Genetic Linkage / Q000235:genetics*; D034381:Hearing Loss / Q000235:genetics*; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D002950:Citrate (si)-Synthase