SOBP is mutated in syndromic and nonsyndromic intellectual disability and is highly expressed in the brain limbic system.

Intellectual disability (ID) affects 1%-3% of the general population. We recently reported on a family with autosomal-recessive mental retardation with anterior maxillary protrusion and strabismus (MRAMS) syndrome. One of the reported patients with ID did not have dysmorphic features but did have temporal lobe epilepsy and psychosis. We report on the identification of a truncating mutation in the SOBP that is responsible for causing both syndromic and nonsyndromic ID in the same family. The protein encoded by the SOBP, sine oculis binding protein ortholog, is a nuclear zinc finger protein. In mice, Sobp (also known as Jxc1) is critical for patterning of the organ of Corti; one of our patients has a subclinical cochlear hearing loss but no gross cochlear abnormalities. In situ RNA expression studies in postnatal mouse brain showed strong expression in the limbic system at the time interval of active synaptogenesis. The limbic system regulates learning, memory, and affective behavior, but limbic circuitry expression of other genes mutated in ID is unusual. By comparing the protein content of the +/jc to jc/jc mice brains with the use of proteomics, we detected 24 proteins with greater than 1.5-fold differences in expression, including two interacting proteins, dynamin and pacsin1. This study shows mutated SOBP involvement in syndromic and nonsyndromic ID with psychosis in humans.

Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss.

Age-related hearing loss (AHL) in common inbred mouse strains is a genetically complex quantitative trait. We found a synonymous single-nucleotide polymorphism in exon 7 of Cdh23 that shows significant association with AHL and the deafness modifier mdfw (modifer of deafwaddler). The hypomorphic Cdh23(753A) allele causes in-frame skipping of exon 7. Altered adhesion or reduced stability of CDH23 may confer susceptibility to AHL. Homozygosity at Cdh23(753A) or in combination with heterogeneous secondary factors is a primary determinant of AHL in mice.

Ectopic mineralization in the middle ear and chronic otitis media with effusion caused by RPL38 deficiency in the Tail-short (Ts) mouse.

Inflammation of the middle ear cavity (otitis media) and the abnormal deposition of bone at the otic capsule are common causes of conductive hearing impairment in children and adults. Although a host of environmental factors can contribute to these conditions, a genetic predisposition has an important role as well. Here, we analyze the Tail-short (Ts) mouse, which harbors a spontaneous semi-dominant mutation that causes skeletal defects and hearing loss. By genetic means, we show that the Ts phenotypes arise from an 18-kb deletion/insertion of the Rpl38 gene, encoding a ribosomal protein of the large subunit. We show that Ts mutants exhibit significantly elevated auditory-brain stem response thresholds and reduced distortion-product otoacoustic emissions, in the presence of normal endocochlear potentials and typical inner ear histology suggestive of a conductive hearing impairment. We locate the cause of the hearing impairment to the middle ear, demonstrating over-ossification at the round window ridge, ectopic deposition of cholesterol crystals in the middle ear cavity, enlarged Eustachian tube, and chronic otitis media with effusion all beginning at around 3 weeks after birth. Using specific antisera, we demonstrate that Rpl38 is an ∼8-kDa protein that is predominantly expressed in mature erythrocytes. Finally, using an Rpl38 cDNA transgene, we rescue the Ts phenotypes. Together, these data present a previously uncharacterized combination of interrelated middle ear pathologies and suggest Rpl38 deficiency as a model to dissect the causative relationships between neo-ossification, cholesterol crystal deposition, and Eustachian tubes in the etiology of otitis media.

Genome-wide linkage analyses identify Hfhl1 and Hfhl3 with frequency-specific effects on the hearing spectrum of NIH Swiss mice.

BACKGROUND: The mammalian cochlea receives and analyzes sound at specific places along the cochlea coil, commonly referred to as the tonotopic map. Although much is known about the cell-level molecular defects responsible for severe hearing loss, the genetics responsible for less severe and frequency-specific hearing loss remains unclear. We recently identified quantitative trait loci (QTLs) Hfhl1 and Hfhl2 that affect high-frequency hearing loss in NIH Swiss mice. Here we used 2f1-f2 distortion product otoacoustic emissions (DPOAE) measurements to refine the hearing loss phenotype. We crossed the high frequency hearing loss (HFHL) line of NIH Swiss mice to three different inbred strains and performed linkage analysis on the DPOAE data obtained from the second-generation populations. RESULTS: We identified a QTL of moderate effect on chromosome 7 that affected 2f1-f2 emissions intensities (Hfhl1), confirming the results of our previous study that used auditory brainstem response (ABR) thresholds to identify QTLs affecting HFHL. We also identified a novel significant QTL on chromosome 9 (Hfhl3) with moderate effects on 2f1-f2 emissions intensities. By partitioning the DPOAE data into frequency subsets, we determined that Hfhl1 and Hfhl3 affect hearing primarily at frequencies above 24 kHz and 35 kHz, respectively. Furthermore, we uncovered additional QTLs with small effects on isolated portions of the DPOAE spectrum. CONCLUSIONS: This study identifies QTLs with effects that are isolated to limited portions of the frequency map. Our results support the hypothesis that frequency-specific hearing loss results from variation in gene activity along the cochlear partition and suggest a strategy for creating a map of cochlear genes that influence differences in hearing sensitivity and/or vulnerability in restricted portions of the cochlea.

The TRPML3 channel: from gene to function.

TRPML3 is a transient receptor potential (TRP) channel that is encoded by the mucolipin 3 gene (MCOLN3), a member of the small mucolipin gene family. Mcoln3 shows a broad expression pattern in embryonic and adult tissues that includes differentiated cells of skin and inner ear. Dominant mutant alleles of murine Mcoln3 cause embryonic lethality, pigmentation defects and deafness. The TRPML3 protein features a six-transmembrane topology and functions as a Ca(2+) permeable inward rectifying cation channel that is open at sub-physiological pH and closes as the extracytosolic pH becomes more acidic. TRPML3 localizes to the plasmamembrane and to early- and late-endosomes as well as lysosomes. Recent advances suggest that TRPML3 may regulate the acidification of early endosomes, hence playing a critical role in the endocytic pathway.

Jxc1/Sobp, encoding a nuclear zinc finger protein, is critical for cochlear growth, cell fate, and patterning of the organ of corti.

The mouse cochlea emerges from the ventral pole of the otocyst to form a one and three-quarter coil. Little is known about the factors that control the growth of the cochlea. Jackson circler (jc) is a recessive mutation causing deafness resulting from a growth arrest of the cochlea duct at day 13.5 of embryonic development. Here, we identify the vertebrate homolog of the Drosophila Sobp (sine oculis-binding protein) gene (named Jxc1) in the jc locus. Jxc1 encodes a nuclear protein that has two FCS-type zinc finger domains (PS51024) and bears nuclear localization signals and highly conserved sequence motifs. Transiently expressed wild-type protein is targeted to the nucleus, but mutant isoforms were mislocalized in the cytoplasm. In jc mutants, the cellular patterning of the organ of Corti is severely disrupted, exhibiting supernumerary hair cells at the apex, showing mirror-image duplications of tunnel of Corti and inner hair cells, and expressing ectopic vestibular-like hair cells within Kölliker's organ. Jxc1 mRNA was detected in inner ear sensory hair cells, supporting cells, and the acoustic ganglia. Expression was also found in the developing retina, olfactory epithelium, trigeminal ganglion, and hair follicles. Collectively, our data support a role for Jxc1 in controlling a critical step in cochlear growth, cell fate, and patterning of the organ of Corti.

TRPML3 mutations cause impaired mechano-electrical transduction and depolarization by an inward-rectifier cation current in auditory hair cells of varitint-waddler mice.

TRPML3 (mucolipin-3) belongs to one of the transient-receptor-potential (TRP) ion channel families. Mutations in the Trpml3 gene cause disorganization of the stereociliary hair bundle, structural aberrations in outer and inner hair cells and stria vascularis defects, leading to deafness in the varitint-waddler (Va) mouse. Here we refined the stereociliary localization of TRPML3 and investigated cochlear hair cell function in varitint-waddler (Va(J)) mice carrying the TRPML3 mutations. Using a TRPML3-specific antibody we detected a approximately 68 kDa protein with near-equal expression levels in cochlea and vestibule of wild-type and Va(J) mutants. At postnatal days 3 and 5, we observed abundant localization of TRPML3 at the base of stereocilia near the position of the ankle links. This stereociliary localization domain was absent in Va(J) heterozygotes and homozygotes. Electrophysiological recordings revealed reduced mechano-electrical transducer currents in hair cells from Va(J)/+ and Va(J)/Va(J) mice. Furthermore, FM1-43 uptake and [(3)H]gentamicin accumulation were decreased in hair cells in cultured organs of Corti from Va(J)/+ and Va(J)/Va(J) mice. We propose that TRPML3 plays a critical role at the ankle-link region during hair-bundle growth and that an adverse effect of mutant TRPML3 on bundle development and mechano-electrical transduction is the main cause of hearing loss in Va(J)/+ mutant mice. Outer hair cells of Va(J)/Va(J) mice additionally had depolarized resting potentials due to an inwardly rectifying leak conductance formed by the mutant channels, leading over time to hair-cell degeneration and contributing to their deafness. Our findings argue against TRPML3 being a component of the hair-cell transducer channel.

TRPML3 and hearing loss in the varitint-waddler mouse.

TRPML3 (also known as mucolipin-3, MCOLN3) belongs to the small family of TRPML ion channel proteins. The mammalian Trpml3 gene encodes a protein of 553 amino acids with short amino and carboxy termini and a transient receptor potential motif spanning from the third to the sixth trans membrane domain. Dominant mutant alleles of Trpml3 cause hearing loss, circling behaviour, pigmentation defects and embryonic lethality in the varitint-waddler (Va) mouse. In the inner ear these mutations cause a reduction or loss of endocochlear potentials, compound action potentials, and auditory-evoked brain stem responses. The hearing phenotype is associated with defects in the cochlea that include disorganization and fusion of stereocilia, distortions at the apical and distal regions of inner and outer hair cells, and loss of pigmented intermediate cells in the stria vascularis. In hair cells the TRPML3 protein is targeted to cytoplasmic vesicles and to the plasma membrane of stereocilia. Both the sub-cellular localization of TRPML3 and the mutant phenotype suggest that TRPML3 is critical for stereocilia bundle formation during development and may function during endocytosis or exocytosis.

Single nucleotide polymorphisms in the cadherin 23 (CDH23) gene in Polish workers exposed to industrial noise.

Single nucleotide polymorphisms (SNPs) are the most frequent type of variation in the human genome and may underlie differential susceptibility to common genetic diseases. A candidate gene for susceptibility to noise-induced hearing loss (NIHL) is Cadherin 23 (CDH23). This study aimed to analyze genetic variation in the CDH23 gene in a group of 10 individuals derived from a cohort of 949 workers exposed to noise, and consisted of five persons from each of the resistant and susceptible extremes. DNA samples were collected and the coding exons of CDH23 were sequenced. We identified a total of 35 SNPs: 11 amino acid substitutions, 8 silent nucleotide changes, and 16 substitutions in intervening sequences. Ten of the 11 amino acid substitutions were previously shown also to segregate in a Cuban population. The nonsynonymous SNPs localized to the part of the gene encoding the extracellular domain of Cadherin 23, in particular ectodomains 5, 13, 14, 15, 16, 17, 19, and 22. One amino acid change occurred at a conserved position in ectodomain 5. Our results provide a framework for future study of polymorphisms in CDH23 as risk factor for NIHL.

Normal hearing in alpha-galactosidase A-deficient mice, the mouse model for Fabry disease.

Fabry disease (OMIM 301500) is a rare X-linked recessive disorder caused by mutations in the alpha-galactosidase gene (Gla). Loss of Gla activity leads to the abnormal accumulation of glycosphingolipids in lysosomes of predominantly vascular endothelial cells. Clinically the disorder presents with angiokeratomas, clouding of the cornea, and renal, cardiac, and cerebrovascular complications. In addition, there is an increased incidence of sensorineural hearing loss in Fabry patients. In this study, we investigated the loss of alpha-galactosidase A activity on hearing function in Gla-deficient mice (Gla(tm1Kul)). Gla mRNA was readily detected in the cochlea of 2- and 12-month old C57BL/6J and C3HeB/FeJ mice. The targeted allele was introgressed to the normal hearing C3HeB/FeJ strain to eliminate confounding genetic background effects. Auditory brain stem responses (ABR) to click, 8-, 16-, and 32 kHz stimuli measured at regular intervals from animals at the N4 backcross generation and from N4F1 hybrids demonstrated normal hearing in hemizygous and homozygous mutant mice up to 76 weeks of age. By histological criteria, the cyto-architecture of the mutant cochlea showed a normal appearance. The data demonstrate that in the mouse the loss of alpha-galactosidase A activity is genetically or biochemically buffered and not sufficient per se to cause an appreciable degree of hearing impairment.

Strain background effects and genetic modifiers of hearing in mice.

Genetic modifiers can be detected in mice by looking for strain background differences in inheritance or phenotype of a mutation. They can be mapped by analyses of appropriate linkage crosses and congenic lines, and modifier genes of large effect can be identified by positional-candidate gene testing. Inbred strains of mice vary widely in onset and severity of age-related hearing loss (AHL), an important consideration when assessing hearing in mutant mice. At least 8 mapped loci and a mitochondrial variant (mt-Tr) are known to contribute to AHL in mouse strains; one locus (ahl) has been identified as a variant of the cadherin 23 gene (Cdh23(753A/G)). This variant also was shown to modify hearing loss associated with the Atp2b2(dfw-2J) and Mass1(frings) mutations. The hearing modifier (Moth1) of tubby (Tub(tub)) mutant mice was shown to be a strain variant of the Mtap1a gene. Human hearing modifiers include DFNM1, which suppresses recessive deafness DFNB26, and a nuclear gene that modulates the severity of hearing loss associated with a mitochondrial mutation. Recently, a variant of the human ATP2B2 gene was shown to exacerbate hearing loss in individuals homozygous for a CDH23 mutation, similar to the Atp2b2(dfw-2J)-Cdh23(753A/G) interaction affecting hearing in mice. Because modifier genes and digenic inheritance are not always distinguishable, we also include in this review several examples of digenic inheritance of hearing loss that have been reported in both mice and humans.

Mapping quantitative trait loci for hearing loss in Black Swiss mice.

In common inbred mouse strains, hearing loss is a highly prevalent quantitative trait, which is mainly controlled by the Cdh23(753A) variant and alleles at numerous other strain-specific loci. Here, we investigated the genetic basis of hearing loss in non-inbred strains. Mice of Swiss Webster, CF-1, NIH Swiss, ICR, and Black Swiss strains exhibited hearing profiles characteristic of progressive, sensorineural hearing impairment. In particular, CF-1, Black Swiss, and NIH Swiss mice showed early-onset hearing impairment, ICR and Swiss Webster mice expressed a delayed-onset hearing loss, and NMRI mice had normal hearing. By quantitative trait locus (QTL) mapping, two significant QTLs were identified underlying hearing loss in Black Swiss mice: one QTL mapped to chromosome (chr) 10 (named ahl5, LOD 8.9, peak association 35-42 cM) and a second QTL localized to chr 18 (ahl6, LOD 3.8, 38-44 cM). Ahl5 and ahl6 account for 61% and 32% of the variation in the backcross, respectively. Cadherin 23 (Cdh23) and protocadherin 15 (Pcdh15), mapping within the 95% confidence interval of ahl5, bear nucleotide polymorphisms in coding exons, but these appear to be unrelated to the hearing phenotype. Haplotype analyses across the Cdh23 locus demonstrated the phylogenetic relationship between Black Swiss and common inbred strains.

Cochlear developmental defect and background-dependent hearing thresholds in the Jackson circler (jc) mutant mouse.

Jackson circler (jc) is a spontaneous, recessive mouse mutation that results in circling behavior and an impaired acoustic startle response. In this study, we refined the phenotypic and genetic parameters of the original jc mutation and characterized a new mutant allele, jc(2J). In open-field behavior tests, homozygous jc mutants exhibited abnormal circling and ambulatory behavior that was indistinguishable from that of phenotypically similar mutants with defects in the vestibule of the inner ear. The jc/jc and jc(2J)/jc(2J) mice had stable elevated auditory-evoked brainstem response (ABR) thresholds at the 16kHz stimulus of 88+/-9dB sound pressure levels (SPL) and 43+/-11dB SPL, respectively. Peak latencies and peak time intervals were normal in jc mutants. The jc mice showed no measurable distortion-product otoacoustic emissions (DPOAEs) above the system noise floor. In the mutant cochlea, the apical turn failed to form due to the developmental growth arrest of the cochlear duct at the level of the first turn at gestational day 13.5. In a large intrasubspecific intercross, jc localized to a 0.2cM interval at position 25cM on chromosome 10, which is homologous to the human 6q21 region. On CZECHII/Ei and CAST/Ei backgrounds jc/jc mutant hearing thresholds at the 16kHz stimulus were significantly lower than those observed on the C57BL/6J background, with means of 62+/-22dB SPL and 55+/-18dB SPL, respectively. Genome-wide linkage scans of backcross, intercross, and congenic progeny revealed a complex pattern of genetic and stochastic effects.

Sustained cadherin 23 expression in young and adult cochlea of normal and hearing-impaired mice.

Cadherin 23 encodes a single-pass transmembrane protein with 27 extracellular cadherin-domains and localizes to stereocilia where it functions as an inter-stereocilia link. Cadherin 23-deficient mice show congenital deafness in combination with circling behavior as a result of organizational defects in the stereocilia hair bundle; common inbred mouse strains carrying the hypomorphic Cdh23(753A) allele are highly susceptible to sensorineural hearing loss. Here, we show that an antibody (N1086) directed against the intracellular carboxyterminus reacts specifically with cadherin 23 and detects with high sensitivity the isoform devoid of the peptide encoded by exon 68 (CDH23Delta68). Cochlea, vestibule, eye, brain and testis produce the CDH23Delta68 isoform in abundance and form moieties with different molecular weight due to variations in glycosylation content. In the cochlea, CDH23Delta68 expression is highest at postnatal day 1 (P1) and P7; expression is down regulated through P14 and P21 and persists at a low steady-state level throughout adulthood (P160). Furthermore, CDH23Delta68 expression levels in young and adult cochlea are similar among normal and hearing deficient strains (C3HeB/FeJ, C57BL/6J and BUB/BnJ). Finally, by immunofluorescence using an antibody (Pb240) specific for ectodomain 14, we show that cadherin 23 localizes to stereocilia during hair bundle development in late gestation and early postnatal days. Cadherin 23-specific labeling becomes weaker as the hair bundle matures but faint labeling concentrated near the top of stereocilia is still detectable at P35. No labeling of cochlea stereocilia was observed with N1086. In conclusion, our data describe a cadherin 23-specific antibody with high affinity to the CDH23Delta68 isoform, reveal a dynamic cochlea expression and localization profile and show sustained cadherin 23 levels in adult cochlea of normal and hearing-impaired mice.

Genetic analyses of the mouse deafness mutations varitint-waddler (Va) and jerker (Espnje).

Genetic studies on spontaneous mouse mutants with hearing defects have provided important insights into the function of genes expressed in inner ear hair cells. Here we report on our genetic analyses of the deaf mutants varitint-waddler (Va) and jerker (Espnje). A high-resolution genetic map localizes VaJ to a 0.14 +/- 0.08 cM region between D3Mit85 and D3Mit259 on distal chromosome 3. By comparative mapping, the human ortholog resides at 1p22.3 between markers D1S3449 and D1S2252. To study the effect of different genetic backgrounds on the hearing phenotype, Espnje and VaJ were crossed to various inbred strains. Auditory-evoked brainstem response tests on F2 progeny demonstrate that expression, inheritance, and penetrance of the hearing phenotype are solely controlled by the mutant allele. To test for a genetic interaction between Espnje and Cdh23v, auditory function was analyzed in double heterozygotes; no significant increases of thresholds of sound pressure levels were observed. The results establish the framework for cloning the Va gene and provide valuable insights into the genetics of deafness mutations in the mouse.

A new spontaneous mutation in the mouse Ames waltzer gene, Pcdh15.

A recessive deafness mutation in the mouse arose spontaneously and was identified in a colony segregating a null allele of the gastrin-releasing peptide receptor (Grpr) locus. Auditory-evoked brain stem response measurements revealed deafness in 7-week-old affected mice. By linkage analyses, the mutant phenotype was mapped near marker D10Mit186 and the protocadherin gene Pcdh15. As shown by complementation testing, the new mutation is allelic with Ames waltzer (Pcdh15(av)). Sequencing mutant-derived brain Pcdh15 cDNAs identified the insertion of a cytosine residue at nucleotide position c2099 (2099insC), which results in a frame-shift and premature stop codon. Abnormal stereocilia on inner and outer hair cells of the organ of Corti were identified by scanning electron microscopy as early as postnatal day 0 and cross-sectional histology revealed severe neuroepithelial degeneration in cochleas of 30-50-day-old mutants. The new allele of Ames waltzer, designated Pcdh15(av-Jfb), may aid in studying the histopathology associated with Usher syndrome type 1F, which is caused by a functional null allele of PCDH15.

Polygenic inheritance of sensorineural hearing loss (Snhl2, -3, and -4) and organ of Corti patterning defect in the ALR/LtJ mouse strain.

Progressive sensorineural hearing loss in humans is a common and debilitating impairment. Sensorineural deafness in inbred strains of mice is a similarly common and genetically diverse phenotype providing experimental models to study the underlying genetics and the biological effects of the risk factors. Here, we report that ALR/LtJ mice develop early-onset profound sensorineural hearing loss as evidenced by high-to-low frequency hearing threshold shifts, absent distortion-product otoacoustic emissions, and normal endocochlear potentials. Linkage analyses of a segregating backcross revealed three novel quantitative trait loci named sensorineural hearing loss (Snhl) -2, -3, and -4. The QTLs achieved very high LOD scores with markers on chromosome 1 (Snhl2, LOD: 12), chromosome 6 (Snhl3, LOD: 24) and chromosome 10 (Snhl4, LOD: 11). Together, they explained 90% of the phenotypic variance. While Snhl2 and Snhl3 affected hearing thresholds across a broad range of test frequencies, Snhl4 caused primarily high-frequency hearing loss. The hearing impairment is accompanied by an organ of Corti patterning defect that is characterized by the ectopic expression of supernumerary outer hair cells organized in rows along the abneural site of the sensory epithelium in the presence of unaltered planar polarity and otherwise normal cochlear duct morphology. Cloning the Snhl2, -3, and -4 genes in the ALR/LtJ mice may provide important genetic and mechanistic insights into the pathology of human progressive sensorineural deafness.

High-frequency sensorineural hearing loss and its underlying genetics (Hfhl1 and Hfhl2) in NIH Swiss mice.

Studies using inbred strains of mice have been invaluable for identifying alleles that adversely affect hearing. However, the efficacy of those studies is limited by the phenotypes that these strains express and the alleles that they segregate. Here, by selectively breeding phenotypically and genetically heterogeneous NIH Swiss mice, we generated two lines-the all-frequency hearing loss (AFHL) line and the high-frequency hearing loss (HFHL) line-with differential hearing loss. The AFHL line exhibited characteristics typical of severe, early-onset, sensorineural hearing impairment. In contrast, the HFHL line expressed a novel early-onset, mildly progressive, and frequency-specific sensorineural hearing loss. By quantitative trait loci (QTLs) analyses in these two lines, we identified QTLs on chromosomes 7, 8, and 10 that significantly affected hearing function. The loci on chromosomes 7 and 8 (Hfhl1 and Hfhl2, respectively) are novel and appear to adversely affect only high frequencies (≥30 kHz). Mice homozygous for NIH Swiss alleles at either Hfhl1 or Hfhl2 have 32-kHz auditory-evoked brain stem response thresholds that are 8-14 dB SPL higher than the corresponding heterozygotes. DNA sequence analyses suggest that both the Cdh23(ahl) and Gipc3(ahl5) variants contribute to the chromosome 10 QTL detected in the AFHL line. The frequency-specific hearing loss indicates that the Hfhl1 and Hfhl2 alleles may affect tonotopic development. In addition, dissecting the underlying complex genetics of high-frequency hearing loss may prove relevant in identifying less severe and common forms of hearing impairment in the human population.

Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human.

Sensorineural hearing loss affects the quality of life and communication of millions of people, but the underlying molecular mechanisms remain elusive. Here, we identify mutations in Gipc3 underlying progressive sensorineural hearing loss (age-related hearing loss 5, ahl5) and audiogenic seizures (juvenile audiogenic monogenic seizure 1, jams1) in mice and autosomal recessive deafness DFNB15 and DFNB95 in humans. Gipc3 localizes to inner ear sensory hair cells and spiral ganglion. A missense mutation in the PDZ domain has an attenuating effect on mechanotransduction and the acquisition of mature inner hair cell potassium currents. Magnitude and temporal progression of wave I amplitude of afferent neurons correlate with susceptibility and resistance to audiogenic seizures. The Gipc3(343A) allele disrupts the structure of the stereocilia bundle and affects long-term function of auditory hair cells and spiral ganglion neurons. Our study suggests a pivotal role of Gipc3 in acoustic signal acquisition and propagation in cochlear hair cells.

Phenotype and genetics of progressive sensorineural hearing loss (Snhl1) in the LXS set of recombinant inbred strains of mice.

Progressive sensorineural hearing loss is the most common form of acquired hearing impairment in the human population. It is also highly prevalent in inbred strains of mice, providing an experimental avenue to systematically map genetic risk factors and to dissect the molecular pathways that orchestrate hearing in peripheral sensory hair cells. Therefore, we ascertained hearing function in the inbred long sleep (ILS) and inbred short sleep (ISS) strains. Using auditory-evoked brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements, we found that ISS mice developed a high-frequency hearing loss at twelve weeks of age that progressed to lower frequencies by 26 weeks of age in the presence of normal endocochlear potentials and unremarkable inner ear histology. ILS mice exhibited milder hearing loss, showing elevated thresholds and reduced DPOAEs at the higher frequencies by 26 weeks of age. To map the genetic variants that underlie this hearing loss we computed ABR thresholds of 63 recombinant inbred stains derived from the ISS and ILS founder strains. A single locus was linked to markers associated with ISS alleles on chromosome 10 with a highly significant logarithm of odds (LOD) score of 15.8. The 2-LOD confidence interval spans approximately 4 Megabases located at position 54-60 Mb. This locus, termed sensorineural hearing loss 1 (Snhl1), accounts for approximately 82% of the phenotypic variation. In summary, this study identifies a novel hearing loss locus on chromosome 10 and attests to the prevalence and genetic heterogeneity of progressive hearing loss in common mouse strains.