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Human Molecular Genetics, 2001, Vol. 10, No. 16 1709-1718
© 2001 Oxford University Press

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

Kumar N. Alagramam, Huijun Yuan1, Markus H. Kuehn2, Crystal L. Murcia3, Sigrid Wayne1, C.R. Srikumari Srisailpathy1,5, R. Brian Lowry6, Russell Knaus7, Lut Van Laer8, F.P. Bernier6, Stuart Schwartz3,4, Charles Lee9, Cynthia C. Morton9, Robert F. Mullins2, Arabandi Ramesh1,5, Guy Van Camp8, Gregory S. Hagemen2, Richard P. Woychik10 and Richard J.H. Smith1,+

Department of Pediatrics, Rainbow Babies and Children’s Hospital, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, USA, 1Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA, 2The University of Iowa Center for Macular Degeneration in the Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA, 3Department of Genetics and 4Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH, USA, 5Department of Genetics, University of Madras, Madras, India, 6Department of Genetics, Alberta Children’s Hospital, Calgary, Alberta, Canada, 7Lumsden Clinic, Lumsden, Saskatchewan, Canada, 8Department of Genetics, University of Antwerp, Belgium, 9Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA and 10Lynx Therapeutics Inc., 25861 Industrial Boulevard, Hayward, CA 94545, USA.

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.

+ To whom correspondence shouldbe addressed. Tel: +1 319 356 3612; Fax: +1 319 356 4547; Email: richard-smith@uiowa.edu The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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