Human Molecular Genetics Advance Access published online on November 20, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn395
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Homozygous disruption of PDZD7 by reciprocal translocation in a consanguineous family: a new member of the Usher syndrome protein interactome causing congenital hearing impairment
1 Institute of Human Genetics, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany 2 Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University, Johannes von Müllerweg 6, 55128 Mainz, Germany 3 Division of Communication Disorders, Department of ORL, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
* To whom correspondence should be addressed. Professor Thomas Haaf, Institute of Human Genetics, Johannes Gutenberg University, Langenbeckstrasse 1, Bldg. 601, 55131 Mainz, Germany; Tel: +49 6131 175790; Fax: +49 6131 175690; E-mail: haaf{at}humgen.klinik.uni-mainz.de
Received October 6, 2008; Revised November 18, 2008; Accepted November 18, 2008
A homozygous reciprocal translocation, 46,XY,t(10;11),t(10;11), was detected in a boy with non-syndromic congenital sensorineural hearing impairment. Both parents and their four other children were heterozygous translocation carriers, 46,XX,t(10;11) and 46,XY,t(10;11), respectively. Fluorescence in situ hybridization of region-specific clones to patient chromosomes was used to localize the breakpoints within BAC RP11-108L7 on chromosome 10q24.3 and within BAC CTD2527F12 on chromosome 11q23.3. Junction fragments were cloned by vector ligation and sequenced. The chromosome 10 breakpoint was identified within the PDZ domain containing 7 (PDZD7) gene, disrupting the open reading frame of transcript PDZD7–C (without PDZ domain) and the 5’-UTR of transcript PDZD7-D (with one PDZ and two prolin-rich domains). The chromosome 11 breakpoint was localized in an intergenic segment. RT PCR analysis revealed PDZD7 expression in the human inner ear. A murine Pdzd7 transcript that is most similar in structure to human PDZD7-D is known to be expressed in the adult inner ear and retina. PDZD7 shares sequence homology with the PDZ domain containing genes, USH1C (harmonin) and DFNB31 (whirlin). Allelic mutations in harmonin and whirlin can cause both Usher syndrome (USH1C and USH2D, respectively) and congenital hearing impairment (DFNB18 and DFNB31, respectively). Protein-protein interaction assays revealed the integration of PDZD7 in the protein network related to the human Usher syndrome. Collectively, our data provide strong evidence that PDZD7 is a new autosomal-recessive deafness-causing gene and also a prime candidate gene for Usher syndrome.