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.

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.

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.

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.

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.

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.

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.

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.

Inheritance patterns of progressive hearing loss in laboratory strains of mice.

Positional cloning of mouse deafness mutations uncovered a plethora of proteins that have important functions in the peripheral auditory system in particular in the cochlear organ of Corti and stria vascularis. Most of these mutant variants follow a monogenic form of inheritance and are rare, highly penetrant, and deleterious alleles. Inbred and heterogenous strains of mice, in contrast, present with non-syndromic hearing impairment due to the effects of multiple genes and hypomorphic and less penetrant alleles that are often transmitted in a non-Mendelian manner.

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.

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.

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.

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.

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.

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.

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.

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.

Balanced levels of Espin are critical for stereociliary growth and length maintenance.

Hearing and balance depend on microvilli-like actin-based projections of sensory hair cells called stereocilia. Their sensitivity to mechanical displacements on the nanometer scale requires a highly organized hair bundle in which the physical dimension of each stereocilium is tightly controlled. The length and diameter of each stereocilium are established during hair bundle maturation and maintained by life-long continuing dynamic regulation.

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).

Cellular and molecular function of mucolipins (TRPML) and polycystin 2 (TRPP2).

Mucolipins (transient receptor potential mucolipin, TRPML) and polycystin-2 proteins (transient receptor potential polycystin, TRPP) constitute two small families of cation channels with motif and sequence similarities to the transient receptor potential (TRP) class of non-selective cation channels. Genetic defects in TRPML1 and TRPML3 in humans and in animal models cause the accumulation of large vacuoles, leading to a variety of cellular phenotypes including neurological and neurosensory deficiencies. TRPML1 is a Ca(2+)-, K(+)-, and Na(+)-permeable cation channel sensitive to pH changes, and regulates a critical step in the maturation of late endosomes to lysosomes.

Gene expression profile of the mouse organ of Corti at the onset of hearing.

We describe the generation of an expressed sequence tag (EST) database of the mouse organ of Corti (OC). Over 20,000 independent clones were isolated, analyzed, and grouped into 8690 unique gene clusters. A large pool of novel genes unique to the OC was identified.

Loss of GLUR2 alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor subunit differentially affects remaining synaptic glutamate receptors in cerebellum and cochlear nuclei.

The alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) type of ionotropic glutamate receptor is the major mediator of fast neurotransmission in the brain and spinal cord. Most AMPA receptors are impermeable to calcium because they contain the GluR2 subunit. However, some AMPA receptors lack GluR2 and pass calcium which can mediate synaptic plasticity and, in excess, neurotoxicity.

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.

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.

Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice.

Deafness in spontaneously occurring mouse mutants is often associated with defects in cochlea sensory hair cells, opening an avenue to systematically identify genes critical for hair cell structure and function. The classical semidominant mouse mutant varitint-waddler (Va) exhibits early-onset hearing loss, vestibular defects, pigmentation abnormalities, and perinatal lethality. A second allele, Va(J), which arose in a cross segregating for Va, shows a less severe phenotype.