A new spontaneous mutation in the mouse protocadherin 15 gene

Zheng, Qing Yin; Yu, He; Washington, J. L.; Kisley, Lauren B.; Kikkawa, Yuichiro; Pawlowski, Karen S.; Wright, Charles G.; Alagramam, Kumar N.

doi:10.1016/j.heares.2006.06.010

Cited by 17 publications

(19 citation statements)

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“…The behavior of rats homozygous for the kci mutation is very similar to those described previously in mouse Pcdh15-mutant alleles [4,5,8,17,18]. The mutation in the kci allele is a nonsense mutation (c. 2911 C>T, p. Arg971X) and is predicted to result in truncated PCDH15 protein at the 9th domain of extracellular cadherin domains.…”

Section: Discussionsupporting

confidence: 76%

“…Genetic analysis of mouse Ames waltzer (av) mutation, which causes deafness and vestibular dysfunction associated with degeneration of the inner ear neuroepithelia, identified protocadherin 15 (Pcdh15) as the gene responsible for hearing impairment [5]. Several [4,5,8,17,18]. Extensive analyses of these av mutants show that mutation in Pcdh15 affects hair bundle morphogenesis and polarity [8,12,17] and mechanotransduction [7].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the Kyoto Circling (KCI) Rat Carrying a Spontaneous Nonsense Mutation in the Protocadherin 15 (Pcdh15) Gene

et al. 2009

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Protocadherin-15 (Pcdh15) plays important roles in the morphogenesis and cohesion of stereocilia bundles and in the maintenance of retinal photoreceptor cells. In humans, mutations in PCDH15 cause Usher syndrome type 1F (USH1F) and non-syndromic deafness DFNB23. In mice, repertories of Pcdh15 mutant alleles have been described as Ames waltzer mutations. For further understanding of Pcdh15 function in vivo and to develop better clinical treatment for the disabling symptoms of USH1F and DFNB23 patients, animal models suitable for clinical as well as pharmacological studies are required. Here we report the characterization of a Pcdh15 mutant allele, Kyoto circling, (Pcdh15 kci ) in the rat. Rats homozygous for Pcdh15 kci display circling and abnormal swimming behaviors along with the lack of an auditory-evoked brainstem response at the highest intensities of acoustic stimulation. Positional cloning analysis revealed a nonsense mutation (c. 2911C>T, p. Arg971X) in the Pcdh15 gene, which is predicted to result in the truncation of the PCDH15 protein at the 9th domain of cytoplasmic cadherin domains. Histological study revealed severe defects in cochlear hair cell stereocilia, collapse of the organ of Corti, and marked reduction of ganglion cells in adult Pcdh15 kci mutants. Severe reduction of sensory hair cells was also found in the saccular macula. Since the rat is more advantageous for clinical and pharmacological studies than the mouse, the KCI rat strain may be a better disease model for Pcdh15-deficit USH1F and DFNB23.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Characterization of the Kyoto Circling (KCI) Rat Carrying a Spontaneous Nonsense Mutation in the Protocadherin 15 (Pcdh15) Gene

et al. 2009

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“…The ABR technique has previously been described [33]. In brief, mice aged P40 were anesthetized with an IP injection of ketamine, xylazine, and acepromazine at doses of 40, 5, and 1 mg/kg, respectively.…”

Section: Methodsmentioning

confidence: 99%

Treatment of ear and bone disease in the Phex mouse mutant with dietary supplementation

Wick

Lin

et al. 2017

American Journal of Otolaryngology

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Hypothesis: Phosphorus and vitamin D (calcitriol) supplementation in the Phex mouse, a murine model for endolymphatic hydrops (ELH), will improve otic capsule mineralization and secondarily ameliorate the postnatal development of ELH and sensorineural hearing loss (SNHL). Background: Male Phex mice have X-linked hypophosphatemic rickets (XLH), which includes osteomalacia of the otic capsule. The treatment for XLH is supplementation with phosphorus and calcitriol. The effect of this treatment has never been studied on otic capsule bone and it is unclear if improving the otic capsule bone could impact the mice’s postnatal development of ELH and SNHL. Methods: Four cohortswere studied: 1) wild-type control, 2) Phex control, 3) Phex prevention, and 4) Phex rescue. The control groups were not given any dietary supplementation. The Phex prevention group was supplemented with phosphorus added to its drinking water and intraperitoneal calcitriol frompostnatal day (P) 7–P40. The Phex rescue group was also supplemented with phosphorus and calcium but only from P20 to P40. At P40, all mice underwent auditory brainstem response (ABR) testing, serum analysis, and temporal bone histologic analysis. Primary outcome was otic capsule mineralization. Secondary outcomes were degree of SNHL and presence ELH. Results: Both treatment groups had markedly improved otic capsule mineralization with less osteoid deposition. The improved otic capsule mineralized did not prevent the development of ELH or SNHL. Conclusion: Supplementation with phosphorus and calcitriol improves otic capsule bone morphology in the Phex male mouse but does not alter development of ELH or SNHL.

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“…Auditory brainstem response (ABR) testing was conducted as previously described (Zheng et al, 2006). Briefly, mice aged P21 and older were anesthetized with an intraperitoneal injection of ketamine, xylazine and acepromazine at doses of 40 mg/kg, 5 mg/kg, and 1 mg/ kg, respectively.…”

Section: Auditory-evoked Brainstem Response (Abr)mentioning

confidence: 99%

A mouse model with postnatal endolymphatic hydrops and hearing loss

et al. 2008

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Endolymphatic hydrops (ELH), hearing loss and neuronal degeneration occur together in a variety of clinically significant disorders, including Meniere's disease (MD). However, the sequence of these pathological changes and their relationship to each other are not well understood. In this regard, an animal model that spontaneously develops these features postnatally would be useful for research purposes. A search for such a model led us to the Phex Hyp-Duk mouse, a mutant allele of the Phex gene causing X-linked hypophosphatemic rickets. The hemizygous male (Phex Hyp-Duk /Y) was previously reported to exhibit various abnormalities during adulthood, including thickening of bone, ELH and hearing loss. The reported inner-ear phenotype was suggestive of progressive pathology and spontaneous development of ELH postnatally, but not conclusive. The main focuses of this report are to further characterize the inner ear phenotype in Phex Hyp-Duk /Y mice and to test the hypotheses that (a) the Phex Hyp-Duk /Y mouse develops ELH and hearing loss postnatally, and (b) the development of ELH in the Phex Hyp-Duk /Y mouse is associated with obstruction of the endolymphatic duct (ED) due to thickening of the surrounding bone. Auditory brainstem response (ABR) recordings at various times points and histological analysis of representative temporal bones reveal that Phex Hyp-Duk /Y mice typically develop adult onset, asymmetric, progressive hearing loss closely followed by the onset of ELH. ABR and histological data show that functional degeneration precedes structural degeneration. The major degenerative correlate of hearing loss and ELH in the mutants is the primary loss of spiral ganglion cells. Further, Phex Hyp-Duk /Y mice develop ELH without evidence of ED obstruction, supporting the idea that ELH can be induced by a mechanism other than the blockade of longitudinal flow of endolymphatic fluid, and occlusion of ED is not a prerequisite for the development of ELH in patients.

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A new spontaneous mutation in the mouse protocadherin 15 gene

Cited by 17 publications

References 18 publications

Characterization of the Kyoto Circling (KCI) Rat Carrying a Spontaneous Nonsense Mutation in the Protocadherin 15 (Pcdh15) Gene

Characterization of the Kyoto Circling (KCI) Rat Carrying a Spontaneous Nonsense Mutation in the Protocadherin 15 (Pcdh15) Gene

Treatment of ear and bone disease in the Phex mouse mutant with dietary supplementation

A mouse model with postnatal endolymphatic hydrops and hearing loss

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