title: Haplo-insufficiency revealed in deafwaddler mice when tested for hearing loss and ataxia.
abstract: The auditory and vestibular systems rely on the plasma membrane calcium ATPase, isoform 2 (PMCA2) to extrude calcium that enters the stereocilia during transduction. Mutations in the gene encoding this protein result in recessive sensorineural deafness and ataxia in the deafwaddler mouse. In this study, we report the identification of a new allele of deafwaddler, dfw(3j). This allele contains a 4-nucleotide deletion resulting in a frame-shift and predicted truncation of PMCA2. No protein is detected in dfw(3j) homozygotes. To examine the dependence of auditory and vestibular function on PMCA2 activity, we compared dfw(3j) with another functional null allele, dfw(2j), and the partial loss-of-function allele, dfw. All mice studied were in the good-hearing CBA/CaJ background. Heterozygotes of either functional null allele displayed highly significant hearing loss by auditory-evoked brainstem responses relative to controls (P < 0.0001), particularly at high frequencies (> 24 kHz). Ataxia was also apparent in these mice on an accelerating rotarod (P < 0.05). In contrast, +/dfw mice were not measurably different from controls in either behavioral test. dfw/dfw mice were deaf, but showed less ataxia than dfw(2j)/dfw(2j) or dfw(3j)/dfw(3j) mice. These results demonstrate that hearing loss and ataxia are dependent on gene dosage and PMCA2 dysfunction.
authors.affiliation: The Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, and Graduate Program in Neurobiology and Behavior, University of Washington School of Medicine, Box 357923, Seattle, WA 98195, USA.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: McCullough
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Tempel
mesh_terms: D000054:Acceleration; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001483:Base Sequence; D000252:Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D027682:Cation Transport Proteins; D016057:Evoked Potentials, Auditory, Brain Stem; D017353:Gene Deletion; D018628:Gene Dosage; D006239:Haplotypes; D034381:Hearing Loss / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006579:Heterozygote; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics*; D008969:Molecular Sequence Data; D009043:Motor Activity; D010641:Phenotype; D053499:Plasma Membrane Calcium-Transporting ATPases; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D012333:RNA, Messenger; D053499:Plasma Membrane Calcium-Transporting ATPases; C506959:Atp2b2 protein, mouse; D000252:Calcium-Transporting ATPases