[Cockayne Syndrome].

Cockayne syndrome (CS) is an autosomal recessive disorder characterized by severe photosensitive genodermatosis that is associated with premature aging caused by defects in the UV-induced DNA damage repair system, particularly the transcription-coupled nucleotide excision repair. The clinical features of CS include photosensitivity, a characteristic senile face, significant developmental abnormalities, such as short stature, underweight, and microcephaly, progressive cachexia, severe visual impairment, and sensorineural deafness. CS is clinically classified into type I (classical type), type II (congenital or severe type) and type III (late-onset or adult-onset type). Additionally, there exists a rare form of xerodema pigmentosum-Cockayne syndrome (XP/CS) complex. The incidence of CS is 2.7 in 1,000,000 individuals in Japan and 90% of the cases are type I. Unlike XP, in CS, skin cancer is not known to occur in areas of skin exposed to sunlight. However, we observed a case where solar keratosis developed in adult-onset CS patients (CS type III) with a pathological mutation in the CSB gene. In XP/CS, patients easily develop skin cancer from early childhood in areas of the skin exposed to sunlight.

Xeroderma pigmentosum group E and DDB2, a smaller subunit of damage-specific DNA binding protein: proposed classification of xeroderma pigmentosum, Cockayne syndrome, and ultraviolet-sensitive syndrome.

Xeroderma pigmentosum is a rare photosensitive syndrome that comprises eight different genetic diseases (A to G; variant (V)). Although genotype-phenotype correlations have been evaluated in most XP groups, the relationship between the E subgroup of xeroderma pigmentosum (XP-E) and damage-specific DNA binding protein (DDB) still remained a mystery. Recent studies have provided new insight for XP-E and the role(s) of DDB2, a smaller subunit of DDB. Reclassification studies have confirmed that mutations in DDB2 give rise to XP-E. The mouse model of XP-E demonstrated that DDB2 was well conserved between mouse and human and was critical in controlling proper cell-survival through regulating the tumor suppressor p53-mediated responses after ultraviolet (UV)-irradiation: i.e. defective DDB2 causes the resistance to cell-killing by UV-irradiation due to decreased p53-mediated apoptosis. These phenotypes are unique to XP-E because other XP groups show normal (XP-V) or hypersensitivity (XP-A, B, C, D, F, and G) to UV-irradiation. Thus XP-E is defined as a skin cancer prone disease with unique resistance to UV-irradiation.

Reduced RNA polymerase II transcription in intact and permeabilized Cockayne syndrome group B cells.

Cockayne syndrome (CS) is characterized by increased photosensitivity, growth retardation, and neurological and skeletal abnormalities. The recovery of RNA synthesis is abnormally delayed in CS cells after exposure to UV radiation. Gene-specific repair studies have shown a defect in the transcription-coupled repair (TCR) of active genes in CS cells from genetic complementation groups A and B (CS-A and CS-B). We have analyzed transcription in vivo in intact and permeabilized CS-B cells. Uridine pulse labeling in intact CS-B fibroblasts and lymphoblasts shows a reduction of approximately 50% compared with various normal cells and with cells from a patient with xeroderma pigmentosum (XP) group A. In permeabilized CS-B cells transcription in chromatin isolated under physiological conditions is reduced to about 50% of that in normal chromatin and there is a marked reduction in fluorescence intensity in transcription sites in interphase nuclei. Transcription in CS-B cells is sensitive to alpha-amanitin, suggesting that it is RNA polymerase II-dependent. The reduced transcription in CS-B cells is complemented in chromatin by the addition of normal cell extract, and in intact cells by transfection with the CSB gene. CS-B may be a primary transcription deficiency.