Disease relevance of Pcdh15

• The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene [1].
• Pcdh15 transcripts are also found in the developing eye, dorsal root ganglion, and the dorsal aspect of the neural tube, floor plate and ependymal cells adjacent to the neural canal [2].
• The deaf-circling Ames waltzer (av) mouse harbors a mutation in the protocadherin 15 (Pcdh15) gene and is a model for inner ear defects associated with Usher syndrome type 1F [3].

High impact information on Pcdh15

• Cochlear hair cells in the av mutants show abnormal stereocilia by 10 days after birth (P10) [1].
• Ames waltzer (av) is a recessive mutation found in mice that causes deafness and a balance disorder associated with the degeneration of inner ear neuroepithelia [1].
• Here we report that the gene that harbours the av mutation encodes a novel protocadherin [1].
• This region of mouse chromosome 10 contains Pcdh15, encoding a protocadherin gene that is mutated in ames waltzer and causes deafness and vestibular dysfunction [4].
• We reveal that harmonin also binds to protocadherin 15 [5].

Biological context of Pcdh15

• 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 [6].
• By linkage analyses, the mutant phenotype was mapped near marker D10Mit186 and the protocadherin gene Pcdh15 [7].
• The Ames waltzer (av) mouse mutant is an autosomal recessive deafness mutation on mouse Chromosome 10 [8].
• Ames Waltzer deaf mice have reduced electroretinogram amplitudes and complex alternative splicing of Pcdh15 transcripts [9].
• Analysis of vestibular evoked potentials and angular vestibulo-ocular reflexes revealed a lack of physiologic response to linear and angular acceleratory stimuli in Pcdh15 mutant mice [3].

Anatomical context of Pcdh15

• Expression of Pcdh15 in the inner ear, nervous system and various epithelia of the developing embryo [2].
• Mutation in the protocadherin 15 (Pcdh15) gene causes hair cell dysfunction and is associated with abnormal stereocilia development [10].
• These findings indicate that the mutation in Pcdh15 results in either a functional abnormality in the vestibular receptor organs or that the defects are limited to the vestibular nerve [3].
• To determine the earliest changes and help identify the primary causes of deafness in av, we performed morphological studies in 15-16 day old mutants, just prior to the maturation of the cochlea [11].
• Colocalization of Pcdh15 with harmonin was found at the base of the photoreceptor outer segment, where newly synthesized disk membranes are present [12].

Associations of Pcdh15 with chemical compounds

• 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 [7].
• We have characterized the first allele (Pcdh15(av-nmf19)) of Ames waltzer (av) obtained by N-ethyl-N-nitrosourea (ENU) mutagenesis [10].

Other interactions of Pcdh15

• The mutant locus was mapped to a region on mouse chromosome 10 close to three spontaneous recessive mutations causing deafness: Ames waltzer (av), Waltzer (v), and Jackson circler (jc) [13].

Analytical, diagnostic and therapeutic context of Pcdh15

• The neural retina was dissected from normal pigmented mice at postnatal day (P)0, P5, P7, P20, P40, and P70, and the presence of Pcdh15 was determined by RT-PCR [14].
• Here we describe where the Pcdh15 gene is expressed at specific times during mouse development using RNA in situ hybridization [2].
• Dye uptake was found to be dramatically reduced in Pcdh15 mutants compared to control littermates, suggesting that the mutation affects hair cell function, although structural abnormalities consistent with significant vestibular dysfunction are not apparent by light and scanning electron microscopy in the vestibular neuroepithelia of young animals [3].

References