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Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F

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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    • "To date, seven USH1 loci (USH1B-USH1H) have been identified by linkage analyses of USH1 families. Five of the corresponding genes have been cloned: the actin-based motor protein myosin VIIa (Myo7a, USH1B) (Gibson et al. 1995; Weil et al. 1995); two cadherin-related proteins, otocadherin or Cadherin 23 (Cdh23, USH1D) (Bolz et al. 2001; Bork et al. 2001) and Protocadherin 15 (Pcdh15, USH1F) (Ahmed et al. 2001; Alagramam et al. 2001a); and two scaffold proteins , harmonin (USH1C) (Verpy et al. 2000; Bitner-Glindzicz et al. 2000) and Sans (USH1G) (Kikkawa et al. 2003; Weil et al. 2003). The USH proteins are involved in hair bundle morphogenesis in the inner ear by means of protein– protein interactions. "
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    ABSTRACT: Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. An important finding from mouse models and molecular studies is that the USH proteins are integrated into a protein network that regulates inner ear morphogenesis. To understand further the function of harmonin in the pathogenesis of USH1, we have generated a targeted null mutation Ush1c mouse model. Here, we examine the effects of null mutation of the Ush1c gene on subcellular localization of Myo7a, Pcdh15 and Sans in the inner ear. Morphology and proteins distributions were analysed in cochlear sections and whole mount preparations from Ush1c(-/-) and Ush1c(-/+) controls mice. We observed the same distribution of Myo7a throughout the cytoplasm in knockout and control mice. However, we detected Pcdh15 at the base of stereocilia and in the cuticular plate in cochlear hair cells from Ush1c(+/-) controls, whereas in the knockout Ush1c(-/-) mice, Pcdh15 staining was concentrated in the apical region of the outer hair cells and no defined staining was detected at the base of stereocilia nor in the cuticular plate. We showed localization of Sans in the stereocilia of controls mouse cochlear hair cells. However, in cochleae from Ush1c(-/-) mice, strong Sans signals were detected towards the base of stereocilia close to their insertion point into the cuticular plate. Our data indicate that the disassembly of the USH1 network caused by absence of harmonin may have led to the mis-localization of the Protocadherin 15 and Sans proteins in the cochlear hair cells of Ush1c(-/-) knockout mice.
    International Journal of Experimental Pathology 02/2011; 92(1):66-71. DOI:10.1111/j.1365-2613.2010.00751.x · 2.05 Impact Factor
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    • "A. El-Amraoui and C. Petit 2008). Two cadherins, cadherin 23 and protocadherin 15, underlie the USH1D (Bolz et al. 2001; Bork et al. 2001) and USH1F (Ahmed et al. 2001; Alagramam et al. 2001b) forms, respectively. The three other USH1 genes encode an actin-based motor, myosin VIIa (USH1B) (Weil et al. 1995), a PDZ-domain-containing protein, harmonin (USH1C) (Bitner-Glindzicz et al. 2000; Verpy et al. 2000), and a putative scaffolding protein with ankyrin repeats, sans (USH1G) (Weil et al. 2003). "
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    ABSTRACT: The 6-billion human population provides a vast reservoir of mutations, which, in addition to the opportunity of detecting very subtle defects, including specific cognitive dysfunctions as well as late appearing disorders, offers a unique background in which to investigate the roles of cell-cell adhesion proteins. Here we focus on inherited human disorders involving members of the cadherin superfamily. Most of the advances concern monogenic disorders. Yet, with the development of single nucleotide polymorphism (SNP) association studies, cadherin genes are emerging as susceptibility genes in multifactorial disorders. Various skin and heart disorders revealed the critical role played by desmosomal cadherins in epidermis, hairs, and myocardium, which experience high mechanical stress. Of particular interest in that respect is the study of Usher syndrome type 1 (USH1), a hereditary syndromic form of deafness. Studies of USH1 brought to light the crucial role of transient fibrous links formed by cadherin 23 and protocadherin 15 in the cohesion of the developing hair bundle, the mechanoreceptive structure of the auditory sensory cells, as well as the involvement of these cadherins in the formation of the tip-link, a key component of the mechano-electrical transduction machinery. Finally, in line with the well-established role of cadherins in synaptic formation, maintenance, strength, and plasticity, a growing number of cadherin family members, especially protocadherins, have been found to be involved in neuropsychiatric disorders.
    Cold Spring Harbor perspectives in biology 01/2010; 2(1):a003095. DOI:10.1101/cshperspect.a003095 · 8.23 Impact Factor
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    • "TG and total cholesterol levels are expressed in mg/dl proteins in a wide variety of biological processes. Previous studies of the Usher syndrome and visual abnormalities have shown that PCDH15 is expressed in several tissues including retina, brain, cerebellum, kidney, cochlea and liver (Alagramam et al. 2001a; Rouget-Quermalet et al. 2006). In this study, the expression pattern of PCDH15 in human was consistent with the pattern previously observed in mice (Alagramam et al. 2001b; Rouget-Quermalet et al. 2006). "
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    ABSTRACT: Familial combined hyperlipidemia (FCHL) is a common lipid disorder characterized by the presence of multiple lipoprotein phenotypes that increase the risk of premature coronary heart disease. In a previous study, we identified an intragenic microsatellite marker within the protocadherin 15 (PCDH15) gene to be associated with high triglycerides (TGs) in Finnish dyslipidemic families. In this study we analyzed all four known nonsynonymous SNPs within PCDH15 in 1,268 individuals from Finnish and Dutch multigenerational families with FCHL. Association analyses of quantitative traits for SNPs were performed using the QTDT test. The nonsynonymous SNP rs10825269 resulted in a P = 0.0006 for the quantitative TG trait. Additional evidence for association was observed with the same SNP for apolipoprotein B levels (apo-B) (P = 0.0001) and total cholesterol (TC) levels (P = 0.001). None of the other three SNPs tested showed a significant association with any lipid-related trait. We investigated the expression of PCDH15 in different human tissues and observed that PCDH15 is expressed in several tissues including liver and pancreas. In addition, we measured the plasma lipid levels in mice with loss-of-function mutations in Pcdh15 (Pcdh15(av-Tg) and Pcdh15(av-3J)) to investigate possible abnormalities in their lipid profile. We observed a significant difference in plasma TG and TC concentrations for the Pcdh15(av-3J) carriers when compared with the wild type (P = 0.013 and P = 0.044, respectively). Our study suggests that PCDH15 is associated with lipid abnormalities.
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