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

  title={Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss},
  author={Konrad Noben-Trauth and Qing Yin Zheng and Kenneth R Johnson},
  journal={Nature Genetics},
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 Cdh23753A allele causes in-frame skipping of exon 7. Altered adhesion or reduced stability of CDH23 may confer susceptibility to AHL. Homozygosity at Cdh23753A or in combination with heterogeneous… 

Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans.

Evidence that mutations at these two cadherin loci can interact to cause hearing loss in digenic heterozygotes of both species is provided and data indicate that CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle.

A QTL on Chr 5 modifies hearing loss associated with the fascin-2 variant of DBA/2J mice

Results of the linkage analyses to map quantitative trait loci (QTLs) that modify the severity of hearing loss associated with the D2 strain Fscn2ahl8 allele are presented.

Genetic Modifiers of Hearing Loss in Mice: The Case of Phenotypic Modification in Homozygous Cdh23ahl Age-Related Hearing Loss

The genetic modifiers that contribute to hearing loss susceptibility and resistance in inbred mice and the genetic approaches used to identify the modifiers in the genetic background are described, with emphasis on the AHL mutation of the cadherin 23 gene Cdh23ahl.

Identification of Novel CDH23 Variants Causing Moderate to Profound Progressive Nonsyndromic Hearing Loss

The role of DFNB12 allelic variants of CDH23 in Saudi Arabian patients with autosomal recessive moderate to profound NSHL without any vestibular or retinal dysfunction were investigated for molecular exploration of genes implicated in hearing impairment.

Ahl3, a third locus on mouse chromosome 17 affecting age-related hearing loss.

Modification of human hearing loss by plasma-membrane calcium pump PMCA2.

A heterozygous, hypofunctional variant (V586M) in plasma-membrane calcium pump PMCA2, which is encoded by ATP2B2, was associated with increased loss in the three severely affected siblings.

Progressive Sensorineural Hearing Loss and Normal Vestibular Function in a Dutch DFNB7/11 Family with a Novel Mutation in TMC1

In a Dutch family with autosomal recessive hearing loss, genome-wide single-nucleotide polymorphism analysis mapped the genetic defect to the DFNB7/11 locus and the progressive phenotype resembles the phenotype previously described for families with dominant TMC1 mutations rather than that of families with recessive TMC 1 mutations which invariably cause severe-to-profound prelingual hearing impairment.



Molecular genetics of hearing loss.

A presentation of the various deafness forms based on the site of the primary defect: hair cell defects, nonsensory cell defect, and tectorial membrane anomalies is adopted.

Ahl2, a second locus affecting age-related hearing loss in mice.

The genetic mapping of a second AHL locus in mice (designated Ahl2) that is a major contributor to the 8- to 10-month difference in hearing loss onset times between NOD/LtJ and C57BL/6J mice is reported.

Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D

The identification of a new gene mutated in v, called otocadherin, which encodes a very large, single-pass transmembrane protein, that is a critical component of hair bundle formation is reported and it is shown that during early hair-cell differentiation, stereocilia organization is disrupted in v2J homozygotes.

mdfw: a deafness susceptibility locus that interacts with deaf waddler (dfw).

The identification and characterization of a new allele of deaf waddler (dfw2J) is described and evidence for a hearing susceptibility locus (mdfw) that interacts with dfw is presented, revealing an epistatic relationship between the mdfw and the dfw genes and providing a model system to study nonsyndromic hearing loss in mice.

A major gene affecting age-related hearing loss is common to at least ten inbred strains of mice.

It is shown that the same Chromosome 10 gene (Ahl) is a major contributor to AHL in nine other inbred mouse strains-129P1/ReJ, A/J, BALB/cByJ, BUB/BnJ, C57BR/cdJ, DBA/2J, NOD/LtJ, SKH2/j, and STOCK760.

Identification and in vitro expression of novel CDH23 mutations of patients with Usher syndrome type 1D

It is suggested that in patients with a typical USH1D phenotype, a significant portion ofCDH23 mutations leads to premature termination of translation or loss of numerous amino acid residues, with a high frequency of changes causing aberrant splicing of CDH23 mRNA.

The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions

It is shown here that CDH23 and harmonin form a protein complex that is predicted to disrupt stereocilia bundles and cause deafness in USH1 patients.

Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle

It is proposed that the shaping of the hair bundle relies on a functional unit composed of myosin VIIa, harmonin b and cadherin 23 that is essential to ensure the cohesion of the stereocilia.