A novel splice site mutation in the Cockayne syndrome group A gene in two siblings with Cockayne syndrome

Cockayne syndrome (CS) is mainly caused by mutations in the Cockayne syndrome group A or B (CSA or CSB) genes which are required for a sub-pathway of nucleotide excision repair entitled transcription coupled repair. Approximately 20% of the CS patients have mutations in CSA, which encodes a 44 kDa tryptophane (Trp, W) and aspartic acid (Asp, D) Amino acids (WD) repeat protein. Up to now, nine different CSA mutations have been identified. We examined two Somali siblings 9 and 12 years old with clinical features typical of CS including skin photosensitivity, progressive ataxia, spasticity, hearing loss, central and peripheral demyelination and intracranial calcifications. Molecular analysis showed a novel splice acceptor site mutation, a G to A transition in the -1 position of intervening sequence 6 (g.IVS6-1G>A), in the CSA (excision repair cross-complementing 8 (ERCC8)) gene. IVS6-1G>A results in a new 28 amino acid C-terminus and premature termination of the CSA protein (G184DFs28X). A review of the CSA protein and the 10 known CSA mutations is also presented.