CC2D2A, encoding a coiled-coil and C2 domain protein, causes autosomal-recessive mental retardation with retinitis pigmentosa

Am J Hum Genet. 2008 Apr;82(4):1011-8. doi: 10.1016/j.ajhg.2008.01.021.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • Calcium / metabolism
  • Child, Preschool
  • Chromosome Mapping
  • Chromosomes, Human, Pair 4 / genetics*
  • Consanguinity
  • Cytoskeletal Proteins
  • Exons / genetics
  • Female
  • Frameshift Mutation*
  • Haplotypes
  • Homozygote
  • Humans
  • Intellectual Disability / genetics*
  • Lod Score
  • Male
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Pakistan
  • Pedigree
  • Protein Structure, Tertiary / genetics
  • Proteins / genetics*
  • Proteins / physiology
  • RNA Splicing / genetics*
  • Retinitis Pigmentosa / genetics*


  • CC2D2A protein, human
  • Cytoskeletal Proteins
  • Proteins
  • Calcium