title: CC2D2A, encoding a coiled-coil and C2 domain protein, causes autosomal-recessive mental retardation with retinitis pigmentosa.
abstract: 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 Ca(2+)-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.
authors.affiliation: Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
authors.forename: Abdul
authors.initials: A
authors.lastname: Noor
authors.forename: Christian
authors.initials: C
authors.lastname: Windpassinger
authors.forename: Megha
authors.initials: M
authors.lastname: Patel
authors.forename: Beata
authors.initials: B
authors.lastname: Stachowiak
authors.forename: Anna
authors.initials: A
authors.lastname: Mikhailov
authors.forename: Matloob
authors.initials: M
authors.lastname: Azam
authors.forename: Muhammad
authors.initials: M
authors.lastname: Irfan
authors.forename: Zahid Kamal
authors.initials: ZK
authors.lastname: Siddiqui
authors.forename: Farooq
authors.initials: F
authors.lastname: Naeem
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: Muhammad
authors.initials: M
authors.lastname: Lutfullah
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayub
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002675:Child, Preschool; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D003241:Consanguinity; D003598:Cytoskeletal Proteins; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010154:Pakistan; D010375:Pedigree; D017434:Protein Structure, Tertiary / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D012326:RNA Splicing / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000235:genetics*
chemical_list: C528701:CC2D2A protein, human; D003598:Cytoskeletal Proteins; D011506:Proteins; D002118:Calcium