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CtIP Mutations Cause Seckel and Jawad Syndromes.
PLoS Genet. 2011 Oct; 7(10):e1002310.PG

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+Show Affiliations

Department of Human Genetics and Department of Biomedicine, Aarhus University, Aarhus, Denmark.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21998596

Citation

Qvist, Per, et al. "CtIP Mutations Cause Seckel and Jawad Syndromes." PLoS Genetics, vol. 7, no. 10, 2011, pp. e1002310.
Qvist P, Huertas P, Jimeno S, et al. CtIP Mutations Cause Seckel and Jawad Syndromes. PLoS Genet. 2011;7(10):e1002310.
Qvist, P., Huertas, P., Jimeno, S., Nyegaard, M., Hassan, M. J., Jackson, S. P., & Børglum, A. D. (2011). CtIP Mutations Cause Seckel and Jawad Syndromes. PLoS Genetics, 7(10), e1002310. https://doi.org/10.1371/journal.pgen.1002310
Qvist P, et al. CtIP Mutations Cause Seckel and Jawad Syndromes. PLoS Genet. 2011;7(10):e1002310. PubMed PMID: 21998596.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CtIP Mutations Cause Seckel and Jawad Syndromes. AU - Qvist,Per, AU - Huertas,Pablo, AU - Jimeno,Sonia, AU - Nyegaard,Mette, AU - Hassan,Muhammad J, AU - Jackson,Stephen P, AU - Børglum,Anders D, Y1 - 2011/10/06/ PY - 2010/10/13/received PY - 2011/07/30/accepted PY - 2011/10/15/entrez PY - 2011/10/15/pubmed PY - 2012/2/4/medline SP - e1002310 EP - e1002310 JF - PLoS genetics JO - PLoS Genet. VL - 7 IS - 10 N2 - 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. SN - 1553-7404 UR - https://www.unboundmedicine.com/medline/citation/21998596/CtIP_Mutations_Cause_Seckel_and_Jawad_Syndromes_ L2 - http://dx.plos.org/10.1371/journal.pgen.1002310 DB - PRIME DP - Unbound Medicine ER -