CtIP Mutations Cause Seckel and Jawad Syndromes.

Area of Science:

• Genetics
• Molecular Biology
• Cellular Biology

Background:

• Seckel syndrome is a recessively inherited dwarfism with microcephaly.
• Genetic heterogeneity exists, with ATR, CENPJ, and CEP152 as known disease genes.
• A Seckel syndrome locus (SCKL2) was previously mapped to chromosome 18p11.31-q11.2.

Purpose of the Study:

• Identify the gene responsible for Seckel syndrome at the SCKL2 locus.
• Investigate the molecular mechanisms underlying Seckel syndrome and Jawad syndrome.
• Determine the role of CtIP in DNA damage response and disease pathogenesis.

Main Methods:

• Genetic analysis of Seckel syndrome (SCKL2) and Jawad syndrome families.
• Mutation screening in the CtIP (RBBP8) gene.
• Cellular characterization of patient-derived cell lines, including DNA damage response assays.
• Expression analysis of CtIP variants.

Main Results:

• Identified two mutations in the CtIP gene in SCKL2 and Jawad syndrome families, leading to C-terminally truncated CtIP.
• The SCKL2 family mutation resulted in a dominant-negative CtIP form, while the Jawad family had an exonic frameshift mutation.
• SCKL2 cells showed defective DNA damage-induced single-stranded DNA formation and hypersensitivity to DNA damage.
• Overexpression of truncated CtIP in normal cells mimicked Seckel syndrome cellular phenotypes.

Conclusions:

• CtIP is a novel disease gene for Seckel syndrome and Jawad syndrome.
• Dominant-negative CtIP mutations can cause recessively inherited disorders.
• CtIP dysfunction disrupts DNA damage response pathways, leading to microcephaly and dwarfism.