title: CtIP Mutations Cause Seckel and Jawad Syndromes.
abstract: Seckel syndrome is a recessively inherited dwarfism disorder characterized by microcephaly and a unique head profile. Genetically, it constitutes a heterogeneous condition, with several loci mapped (SCKL1-5) but only three disease genes identified: the ATR, CENPJ, and CEP152 genes that control cellular responses to DNA damage. We previously mapped a Seckel syndrome locus to chromosome 18p11.31-q11.2 (SCKL2). Here, we report two mutations in the CtIP (RBBP8) gene within this locus that result in expression of C-terminally truncated forms of CtIP. We propose that these mutations are the molecular cause of the disease observed in the previously described SCKL2 family and in an additional unrelated family diagnosed with a similar form of congenital microcephaly termed Jawad syndrome. While an exonic frameshift mutation was found in the Jawad family, the SCKL2 family carries a splicing mutation that yields a dominant-negative form of CtIP. Further characterization of cell lines derived from the SCKL2 family revealed defective DNA damage induced formation of single-stranded DNA, a critical co-factor for ATR activation. Accordingly, SCKL2 cells present a lowered apoptopic threshold and hypersensitivity to DNA damage. Notably, over-expression of a comparable truncated CtIP variant in non-Seckel cells recapitulates SCKL2 cellular phenotypes in a dose-dependent manner. This work thus identifies CtIP as a disease gene for Seckel and Jawad syndromes and defines a new type of genetic disease mechanism in which a dominant negative mutation yields a recessively inherited disorder.
authors: Department of Human Genetics and Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors: Per
authors: P
authors: Qvist
authors: Pablo
authors: P
authors: Huertas
authors: Sonia
authors: S
authors: Jimeno
authors: Mette
authors: M
authors: Nyegaard
authors: Muhammad J
authors: MJ
authors: Hassan
authors: Stephen P
authors: SP
authors: Jackson
authors: Anders D
authors: AD
authors: Børglum
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004249:DNA Damage; D004277:DNA, Single-Stranded; D004392:Dwarfism / Q000235:genetics* / Q000473:pathology; D004706:Endodeoxyribonucleases; D016368:Frameshift Mutation; D005799:Genes, Dominant; D005808:Genes, Recessive; D042822:Genomic Instability; D006801:Humans; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004277:DNA, Single-Stranded; D009687:Nuclear Proteins; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human