Alterations in the CSB gene in three Italian patients with the severe form of Cockayne syndrome (CS) but without clinical photosensitivity

Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by postnatal growth failure, mental retardation and otherwise clinically heterogeneous features which commonly include cutaneous photosensitivity. Cultured cells from sun-sensitive CS patients are hypersensitive to ultraviolet (UV) light and, following UV irradiation, are unable to restore RNA synthesis rates to normal levels. This has been attributed to a specific deficiency in CS cells in the ability to carry out preferential repair of damage in actively transcribed regions of DNA. We report here a cellular and molecular analysis of three Italian CS patients who were of particular interest because none of them was sun-sensitive, despite showing most of the features of the severe form of CS, including the characteristic cellular sensitivity to UV irradiation. They all were altered in the CSB gene. The genetically related patients CS1PV and CS3PV were homozygous for the C1436T transition resulting in the change Arg453opal. Patient CS2PV was a compound heterozygote for two new causative mutations, insertions of an A at position 1051 and of TGTC at 2053, leading to truncated proteins of 367 and 681 amino acids. These mutations result in severely truncated proteins, as do many of those that we previously identified in several sun-sensitive CS-B patients. These observations confirm that the CSB gene is not essential for viability and cell proliferation, an important issue to be considered in any speculation on the recently proposed additional function of the CSB protein in transcription. Our investigations provide data supporting the notion that other factors, besides the site of the mutation, influence the type and severity of the CS clinical features.