Hearing loss is the most common sensory deficit in humans. Because the auditory systems of mice and humans are conserved, studies on mouse models have predicted several human deafness genes and identified new genes involved in hearing. The deafwaddler (dfw) mouse mutant is deaf and displays vestibular/motor imbalance. Here we report that the gene encoding a plasma membrane Ca2+-ATPase type 2 pump (Atp2b2, also known as Pmca2) is mutated in dfw. An A-->G nucleotide transition in dfw DNA causes a glycine-to-serine substitution at a highly conserved amino-acid position, whereas in a second allele, dfw2J, a 2-base-pair deletion causes a frameshift that predicts a truncated protein. In the cochlea, the protein Atp2b2 is localized to stereocilia and the basolateral wall of hair cells in wild-type mice, but is not detected in dfw2J mice. This indicates that mutation of Atp2b2 may cause deafness and imbalance by affecting sensory transduction in stereocilia as well as neurotransmitter release from the basolateral membrane. These mutations affecting Atp2b2 in dfw and dfw2J are the first to be found in a mammalian plasma membrane calcium pump and define a new class of deafness genes that directly affect hair-cell physiology.

Mutations in LITAF may account for a significant proportion of CMT1 patients with previously unknown molecular diagnosis and may define a new mechanism of peripheral nerve perturbation leading to demyelinating neuropathy.

The opisthotonos (opt) mutation arose spontaneously in a C57BL/Ks-db2J colony and is the only known, naturally occurring allele of opt. This mutant mouse was first identified based on its ataxic and convulsive phenotype. Genetic and molecular data presented here demonstrate that the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) protein, which serves as an IP3-gated channel to release calcium from intracellular stores, is altered in the opt mutant. A genomic deletion in the IP3R1 gene removes two exons from the IP3R1 mRNA but does not interrupt the translational reading frame. The altered protein is predicted to have lost several modulatory sites and is present at markedly reduced levels in opt homozygotes. Nonetheless, a strong calcium release from intracellular stores can be elicited in cerebellar Purkinje neurons treated with the metabotropic glutamate receptor (mGluR) agonist quisqualate (QA). QA activates Group 1 mGluRs linked to GTP-binding proteins that stimulate phospholipase C and subsequent production of the intracellular messenger IP3, leading to calcium mobilization via the IP3R1 protein. The calcium response in opt homozygotes shows less attenuation to repeated QA application than in control littermates. These data suggest that the convulsions and ataxia observed in opt mice may be caused by the physiological dysregulation of a functional IP3R1 protein.

Mutations within the COCH gene (encoding the cochlin protein) lead to auditory and vestibular impairment in the DFNA9 disorder. In this study, we describe the genetic mapping of progressive autosomal dominant sensorineural hearing loss first affecting high-frequency auditory thresholds within a human pedigree to the long arm of chromosome 14 in band q12. A maximal pairwise LOD score of 7.08 was obtained with marker D14S1021. We identified a c.1625G > T mutation in exon 12 of COCH that co-segregates with auditory dysfunction in the pedigree. The mutation results in a predicted p.C542F substitution at an evolutionarily conserved cysteine residue in the C-terminus of cochlin. The c.1625G > T transversion in COCH exon 12 represents the first reported mutation outside of the LCCL domain which is encoded by exons 4 and 5. The 542F mutant cochlin is translated and secreted by transfected mammalian cells. Western blot analysis under non-reducing and reducing conditions suggests that the 542F mutation alters intramolecular cochlin disulfide bond formation. In the vestibular system, a progressive horizontal canal hypofunction and a probable saccular otolith challenge were detected in family members with the c.1625G > T COCH alteration. Abnormal central oculomotor test results in family members with the c.1625G > T COCH alteration imply a possible central nervous system change not previously noted in DFNA9 pedigrees harboring mutations within the LCCL domain.