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Title

CtIP Mutations Cause Seckel and Jawad Syndromes

AuthorsQvist, Per; Huertas Sánchez, Pablo ; Jimeno, Sonia ; Nyegaard, Mette; Hassan, Muhammad J.; Jackson, Stephen P.; Børglum, Anders D.
KeywordsCell cycle proteins
Microcephaly
Carrier proteins
DNA
Nuclear proteins
RBBP8 protein
Seckel syndrome
Jawad syndrome
Issue Date6-Oct-2011
PublisherPublic Library of Science
CitationPLoS Genetics 7(10): e1002310 (2011)
AbstractSeckel 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.
DescriptionThis is an open-access article distributed under the terms of the Creative Commons Attribution License.
Publisher version (URL)http://dx.doi.org/10.1371/journal.pgen.1002310
URIhttp://hdl.handle.net/10261/49363
DOI10.1371/journal.pgen.1002310
ISSN1553-7390
E-ISSN1553-7404
Appears in Collections:(CABIMER) Artículos
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