Cockayne syndrome type II in a Druze isolate in Northern Israel in association with an insertion mutation in ERCC6

Abstract

Cockayne syndrome (CS) (OMIM #133540) is a rare autosomal recessive disease characterized by severe growth and developmental retardation, progressive neurological dysfunction and symptoms of premature aging. The underlying cause of the disease is a defect in transcription-coupled DNA repair, specifically the nucleotide excision repair (NER) pathway. To date, about half of the reported CS cases have an altered cellular response to UV resulting from mutations in either the CSA or the CSB genes. We have identified a large, highly consanguineous, Druze kindred descended from a single ancestor, with six CS cases. All six of them presented with the congenital severe phenotype that includes severe failure to thrive, severe mental retardation, congenital cataracts, loss of adipose tissue, joint contractures, distinctive face with small, deep-set eyes and prominent nasal bridge, and kyphosis. They had no language skills, could not sit or walk independently, and died by the age of 5 years. Cellular studies of the fibroblasts from three patients showed a significant defect in transcription-coupled DNA repair (TCR) and a marked correction of the abnormal cellular phenotype with a plasmid containing the cDNA of the ERCC6 gene. Molecular studies led to identification of a novel insertion mutation, c.1034-1035insT in exon 5 of the ERCC6 gene (p.Lys345Asnfs*24). This mutation was identified in 1:15 healthy individuals from the same village, indicating an extremely high carrier frequency. Identification of the causative mutation enables comprehensive genetic counseling among the population at risk from this village.