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J Med Genet 43:203-210 doi:10.1136/jmg.2005.035709
  • Original article

The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation

  1. L Basel-Vanagaite1,*,
  2. R Attia2,*,
  3. M Yahav2,
  4. R J Ferland3,
  5. L Anteki2,
  6. C A Walsh3,
  7. T Olender4,
  8. R Straussberg5,
  9. N Magal2,
  10. E Taub1,
  11. V Drasinover2,
  12. A Alkelai2,
  13. D Bercovich6,
  14. G Rechavi7,
  15. A J Simon7,
  16. M Shohat1
  1. 1Department of Medical Genetics, Rabin Medical Centre, Beilinson Campus, Petah Tikva, Israel
  2. 2Felsenstein Medical Research Centre, Petah Tikva, Israel
  3. 3Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, and Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA
  4. 4Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
  5. 5Neurogenetic Clinic, Schneider Children’s Medical Centre of Israel, Petah Tikva, Israel
  6. 6Human Molecular Genetics and Pharmacogenetics, Migal – Galilee Bio-Technology Centre, Kiryat-Shmona, and Tel Hai Academic College, Israel
  7. 7Sheba Cancer Research Centre, Institute of Haematology, The Chaim Sheba Medical Centre, Tel Hashomer, Israel
  1. Correspondence to:
 Dr Lina Basel-Vanagaite
 Department of Medical Genetics, Rabin Medical Centre, Beilinson Campus, Petah Tikva 49100, Israel; basel{at}post.tau.ac.il
  • Received 8 June 2005
  • Accepted 8 July 2005
  • Revised 5 July 2005
  • Published Online First 20 July 2005

Abstract

Background: The molecular basis of autosomal recessive non-syndromic mental retardation (NSMR) is poorly understood, mostly owing to heterogeneity and absence of clinical criteria for grouping families for linkage analysis. Only two autosomal genes, the PRSS12 gene on chromosome 4q26 and the CRBN on chromosome 3p26, have been shown to cause autosomal recessive NSMR, each gene in only one family.

Objective: To identify the gene causing autosomal recessive NSMR on chromosome 19p13.12.

Results: The candidate region established by homozygosity mapping was narrowed down from 2.4 Mb to 0.9 Mb on chromosome 19p13.12. A protein truncating mutation was identified in the gene CC2D1A in nine consanguineous families with severe autosomal recessive NSMR. The absence of the wild type protein in the lymphoblastoid cells of the patients was confirmed. CC2D1A is a member of a previously uncharacterised gene family that carries two conserved motifs, a C2 domain and a DM14 domain. The C2 domain is found in proteins which function in calcium dependent phospholipid binding; the DM14 domain is unique to the CC2D1A protein family and its role is unknown. CC2D1A is a putative signal transducer participating in positive regulation of I-κB kinase/NFκB cascade. Expression of CC2D1A mRNA was shown in the embryonic ventricular zone and developing cortical plate in staged mouse embryos, persisting into adulthood, with highest expression in the cerebral cortex and hippocampus.

Conclusions: A previously unknown signal transduction pathway is important in human cognitive development.

Footnotes

  • * These two authors contributed equally to this work.

  • Published Online First 20 July 2005

  • Competing interests: none declared.