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Alagramam, K. N., Yuan, H., Kuehn, M. H., Murcia, C. L., Wayne, S., Srisailpathy, C. et al. Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F. Hum. Mol. Genet. 10, 1709-1718

Department of Pediatrics, Rainbow Babies and Children's Hospital, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, USA.
Human Molecular Genetics (Impact Factor: 6.68). 09/2001; 10(16):1709-18. DOI: 10.1093/hmg/10.16.1709
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ABSTRACT We have determined the molecular basis for Usher syndrome type 1F (USH1F) in two families segregating for this type of syndromic deafness. By fluorescence in situ hybridization, we placed the human homolog of the mouse protocadherin Pcdh15 in the linkage interval defined by the USH1F locus. We determined the genomic structure of this novel protocadherin, and found a single-base deletion in exon 10 in one USH1F family and a nonsense mutation in exon 2 in the second. Consistent with the phenotypes observed in these families, we demonstrated expression of PCDH15 in the retina and cochlea by RT-PCR and immunohistochemistry. This report shows that protocadherins are essential for maintenance of normal retinal and cochlear function.

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Available from: Markus H Kuehn, Apr 28, 2014
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    • "A mutation in exon 10 of the protocadherin-related 15 (PCDH15) gene (c.1471delG) was previously reported in the Hutterite population of southern Alberta [6]. Our colleagues from southern Alberta were not aware of other individuals with Usher syndrome in the province (R. Brian Lowry, Alberta Children's Hospital, Calgary, Alberta, Canada, January 2012). "
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    ABSTRACT: To identify the genetic defect in a Hutterite population from northern Alberta with Usher syndrome type I. Complete ophthalmic examinations were conducted on two boys and two girls from two related Hutterite families diagnosed with Usher syndrome type I. DNA from patients and their parents was first evaluated for a mutation in exon 10 of the protocadherin-related 15 (PCDH15) gene (c.1471delG), previously reported in southern Alberta Hutterite patients with Usher syndrome (USH1F). Single nucleotide polymorphic linkage analysis was then used to confirm another locus, and DNA was analyzed with the Usher Chip v4.0 platform. Severe hearing impairment, unintelligible speech, and retinitis pigmentosa with varying degrees of visual acuity and visual field loss established a clinical diagnosis of Usher syndrome type I. The patients did not carry the exon 10 mutation in the PCDH15 gene; however, with microarray analysis, a previously reported mutation (c.52C>T; p.Q18X) in the myosin VIIA (MYO7A) gene was found in the homozygous state in the affected siblings. The finding of a MYO7A mutation in two related Hutterite families from northern Alberta provides evidence of genetic heterogeneity in Hutterites affected by Usher syndrome type I.
    Molecular vision 05/2012; 18:1379-83. · 2.25 Impact Factor
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    • "Usher syndrome (USH) is a genetic neurosensory disorder characterized by congenital deafness, variable vestibular dysfunction and progressive retinitis pigmentosa [10], [11]. Among the 9 genes associated with USH, mutations in the genes encoding adhesion molecules, cadherin-23 (CDH23) and protocadherin-15 (PCDH15), the very large G protein-coupled receptor 1 (VLGR1) and clarin-1 are associated to USH1D, USH1F, USH2C and USH3A, respectively [12]–[15]. It has been suggested that these Usher proteins play roles in hair cell development, neurogenesis and synaptogenesis [16]–[19]. "
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    ABSTRACT: The molecular mechanisms underlying hair cell synaptic maturation are not well understood. Cadherin-23 (CDH23), protocadherin-15 (PCDH15) and the very large G-protein coupled receptor 1 (VLGR1) have been implicated in the development of cochlear hair cell stereocilia, while clarin-1 has been suggested to also play a role in synaptogenesis. Mutations in CDH23, PCDH15, VLGR1 and clarin-1 cause Usher syndrome, characterized by congenital deafness, vestibular dysfunction and retinitis pigmentosa. Here we show developmental expression of these Usher proteins in afferent spiral ganglion neurons and hair cell synapses. We identify a novel synaptic Usher complex comprised of clarin-1 and specific isoforms of CDH23, PCDH15 and VLGR1. To establish the in vivo relevance of this complex, we performed morphological and quantitative analysis of the neuronal fibers and their synapses in the Clrn1-/- mouse, which was generated by incomplete deletion of the gene. These mice showed a delay in neuronal/synaptic maturation by both immunostaining and electron microscopy. Analysis of the ribbon synapses in Ames waltzer(av3J) mice also suggests a delay in hair cell synaptogenesis. Collectively, these results show that, in addition to the well documented role for Usher proteins in stereocilia development, Usher protein complexes comprised of specific protein isoforms likely function in synaptic maturation as well.
    PLoS ONE 02/2012; 7(2):e30573. DOI:10.1371/journal.pone.0030573 · 3.23 Impact Factor
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    • "Pcdh15 is widely expressed in multiple tissues, including the brain, cochlea, and vestibule [29]. In the developing cochlea, Pcdh15 was localized to the apical surface of hair cells, supporting cells, outer sulcus cells, and spiral ganglion cells, while mature cochleae express protocadherin 15 only in hair cell stereocilia [30]. "
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    ABSTRACT: Sensorineural hearing loss is one of the most common disabilities in humans. It is estimated that about 278 million people worldwide have slight to extreme hearing loss in both ears, which results in an economic loss for the country and personal loss for the individual. It is thus critical to have a deeper understanding of the causes for hearing loss to better manage and treat the affected individuals. The mouse serves as an excellent model to study and recapitulate some of these phenotypes, identify new genes which cause deafness, and to study their roles in vivo and in detail. Mutant mice have been instrumental in elucidating the function and mechanisms of the inner ear. The development and morphogenesis of the inner ear from an ectodermal layer into distinct auditory and vestibular components depends on well-coordinated gene expression and well-orchestrated signaling cascades within the otic vesicle and interactions with surrounding layers of tissues. Any disruption in these pathways can lead to hearing impairment. This review takes a look at some of the genes and their corresponding mice mutants that have shed light on the mechanism governing hearing impairment (HI) in humans.
    10/2011; 2011:416450. DOI:10.4061/2011/416450
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