CtIP Mutations Cause Seckel and Jawad Syndromes.
CtIP Mutations Cause Seckel and Jawad Syndromes.
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DOI：
10.1371/journal.pgen.1002310
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发表时间：
2011-10
期刊：
影响因子：
4.5
通讯作者：
Børglum AD
中科院分区：
文献类型：
--
作者：
Qvist P;Huertas P;Jimeno S;Nyegaard M;Hassan MJ;Jackson SP;Børglum AD
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. Cellular DNA is frequently damaged through the actions of exogenous and endogenously arising DNA damaging agents. To maintain genome integrity, cells have evolved complex mechanisms to detect DNA damage, signal its presence, and mediate its repair. The importance of such mechanisms is evident because inherited defects in them can cause embryonic lethality or severe genetically inherited diseases. The clinical manifestations of such diseases are complex and include growth delay, mental retardation, skeletal abnormalities, and predisposition to cancer. While most such syndromes are inherited recessively, in some cases they are inherited dominantly. Here, we show that mutations in CtIP/RBBP8 cause related disorders: Seckel and Jawad syndromes. In addition to revealing how mutated CtIP impairs responses to DNA damage in Seckel cells, we establish that, despite the recessive mode of inheritance for this syndrome, the Seckel mutation has a dominant manifestation at the cellular level. To our knowledge, this represents a new form of molecular mechanism for recessive inheritance of a human disease. Furthermore, the aberrantly spliced mRNA is expressed at very low levels and yet significantly impairs cellular functions and causes severe clinical symptoms. This should provide new awareness that even very subtle splice mutations may have pronounced pathogenic potential.
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