CtIP Mutations Cause Seckel and Jawad Syndromes

• DOI: 10.1371/journal.pgen.1002310
• Publication Date: 2011-10-06T21:58:20Z
• Authors: Per Qvist; Pablo Huertas; Sonia Jimeno; Mette Nyegaard; Muhammad J. Hassan; Stephen P. Jackson; Anders D. Børglum
• Keywords: Microcephaly

Seckel syndrome is a recessively inherited dwarfism disorder characterized by microcephaly and unique head profile. Genetically, it constitutes heterogeneous condition, with several loci mapped (SCKL1-5) but only three disease genes identified: the ATR, CENPJ, CEP152 that control cellular responses to DNA damage. We previously locus chromosome 18p11.31-q11.2 (SCKL2). Here, we report two mutations in CtIP (RBBP8) gene within this result expression of C-terminally truncated forms CtIP. propose these are molecular cause observed described SCKL2 family an additional unrelated diagnosed similar form congenital termed Jawad syndrome. While exonic frameshift mutation was found family, carries splicing yields dominant-negative Further characterization cell lines derived from revealed defective damage induced formation single-stranded DNA, critical co-factor for ATR activation. Accordingly, cells present lowered apoptopic threshold hypersensitivity Notably, over-expression comparable variant non-Seckel recapitulates phenotypes dose-dependent manner. This work thus identifies as syndromes defines new type genetic mechanism which dominant negative disorder.