Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 4, 1011-1018, 03 April 2008
doi:10.1016/j.ajhg.2008.01.021
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CC2D2A, Encoding A Coiled-Coil and C2 Domain Protein, Causes Autosomal-Recessive Mental Retardation with Retinitis Pigmentosa
Abdul Noor1, Christian Windpassinger1, 2, Megha Patel1, Beata Stachowiak1, Anna Mikhailov1, Matloob Azam3, Muhammad Irfan4, Zahid Kamal Siddiqui5, Farooq Naeem6, Andrew D. Paterson7, Muhammad Lutfullah8, John B. Vincent1, 
, 
and Muhammad Ayub9
1 Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada
2 Institute of Human Genetics, Medical University of Graz, Graz 8010, Austria
3 Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan
4 Lahore Institute of Research and Development, Lahore 54000, Pakistan
5 Postgraduate Medical Institute and Lahore General Hospital, Lahore 54000, Pakistan
6 Sheikh Zayed Hospital, Rahim Yar Khan 64200, Pakistan
7 Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
8 Mayo Hospital, Lahore 54000, Pakistan
9 St. Luke's Hospital, Middlesborough TS4 3AF, UK
Corresponding authorAbstract
Autosomal-recessive inheritance is believed to be relatively common in mental retardation (MR), although only four genes for nonsyndromic autosomal-recessive mental retardation (ARMR) have been reported. In this study, we ascertained a consanguineous Pakistani family with ARMR in four living individuals from three branches of the family, plus an additional affected individual later identified as a phenocopy. Retinitis pigmentosa was present in affected individuals, but no other features suggestive of a syndromic form of MR were found. We used Affymetrix 500K microarrays to perform homozygosity mapping and identified a homozygous and haploidentical region of 11.2 Mb on chromosome 4p15.33-p15.2. Linkage analysis across this region produced a maximum two-point LOD score of 3.59. We sequenced genes within the critical region and identified a homozygous splice-site mutation segregating in the family, within a coiled-coil and C2 domain-containing gene, CC2D2A. This mutation leads to the skipping of exon 19, resulting in a frameshift and a truncated protein lacking the C2 domain. Conservation analysis for CC2D2A suggests a functional domain near the C terminus as well as the C2 domain. Preliminary functional studies of CC2D2A suggest a possible role in Ca2+-dependent signal transduction. Identifying the function of CC2D2A, and a possible common pathway with CC2D1A, in correct neuronal development and functioning may help identify possible therapeutic targets for MR.
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