Origin of Vestibular Dysfunction in Usher Syndrome Type 1B

Sun, John C.; Alphen, Adriaan M. van; Wagenaar, M.; Huygen, P.L.M.; Hoogenraad, Casper C.; Hasson, Tama; Koekkoek, S.K.E.; Bohne, Barbara A.; Zeeuw, Chris I. De

doi:10.1006/nbdi.2000.0358

Cited by 10 publications

(16 citation statements)

References 28 publications

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“…In addition, the lack of a normal synergy of optokinetic and vestibular signals during ambulation in light could prevent the mutant from optimally Btuning^its optokinetic system. However, wholly normal optokinetic performance can coexist with complete peripheral vestibular failure (Sun et al 2001), so our behavioral results do not exclude the possibility that Pcdh15 plays some role in the development or subsequent function of the central pathways.…”

Section: Discussionmentioning

confidence: 77%

Characterization of Vestibular Dysfunction in the Mouse Model for Usher Syndrome 1F

Alagramam

Stahl

Jones

et al. 2005

JARO

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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. Earlier studies showed altered cochlear hair cell morphology in young av mice. In contrast, no structural abnormality consistent with significant vestibular dysfunction in young av mice was observed. Light and scanning electron microscopic studies showed that vestibular hair cells from presumptive null alleles Pcdh15 av-Tg and Pcdh15 av-3J are morphologically similar to vestibular sensory cells from control littermates, suggesting that the observed phenotype in these alleles might be a result of a central, rather than peripheral, defect. In the present study, a combination of physiologic and anatomic methods was used to more thoroughly investigate the source of vestibular dysfunction in Ames waltzer mice. 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. Optokinetic reflex function was diminished but still present in the mutant animals, suggesting that the defect is primarily peripheral in nature. 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. AM1-43 dye uptake has been shown to correlate with normal transduction function in hair cells. 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.

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Section: Discussionmentioning

confidence: 77%

Characterization of Vestibular Dysfunction in the Mouse Model for Usher Syndrome 1F

Alagramam

Stahl

Jones

et al. 2005

JARO

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“…We found that the OKR gains of both USH1B patients and sh1 mice were not significantly different from those of normal age‐matched subjects and heterozygous littermate mice, respectively. The OKR phase values of the sh1 mice were also not significantly different from their control littermates 14. It has been well documented in human, mouse, and other mammalian species that cerebellar degeneration has a profound effect on both the gain and phase of their OKR 26–29.…”

Section: Resultsmentioning

confidence: 68%

“…Due to the overwhelming radiographic evidence of cerebellar abnormalities in USH1 patients, we first determined if myosin‐VIIa is expressed in the human cerebellum. Both our immunocytochemical data and Western blot analysis showed that neither the human nor mouse cerebellum expressed myosin‐VIIa 14. To determine the cerebellar function of USH1B patients and sh1 mice at the behavioral level, we investigated their optokinetic reflex (OKR).…”

Section: Resultsmentioning

confidence: 98%

“…At the present time, of all the HVDDs, the pathophysiology of the vestibular dysfunction in USH1B patients has been the best characterized. The reason is that mutant mouse technology has been used to study this human syndrome 14. We have developed techniques in which we can determine the exact origin and mechanism of vestibular dysfunction in a mutant mouse model and correlate our findings to a human hereditary vestibular disease 14…”

Section: Overviewmentioning

confidence: 99%

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Hereditary Familial Vestibular Degenerative Diseases

Sun

Alphen

Wagenaar

et al. 2001

Annals of the New York Academy of Sciences

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“…These mice run in one direction in a circular pattern, occasionally becoming violent. The animal model for vertigo most studied probably is the shaker‐1 mouse, first described by Deol and later characterized to be a mouse model for Usher syndrome type 1B …”

Section: Introductionmentioning

confidence: 99%