Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3):: Xeroderma pigmentosum without and with Cockayne syndrome

Defects in the xeroderma pigmentosum type B (XPB) gene (ERCC3), a DNA helicase involved in nucleotide excision repair (NER) and an essential subunit of the basal transcription factor, TFIIH, have been described in only three families. We report three new XPB families: one has two sisters with relatively mild xeroderma pigmentosum (XT) symptoms not previously associated with XPB mutations and two have severe XP/Cockayne syndrome (CS) complex symptoms. All XP-B cells had reduced NER and post,ultraviolet (UV) cell viability. Surprisingly, cells from the milder XP sisters had the same missense mutation (c.296T > C, p.F99S) that was previously reported in two mild XP/CS complex brothers. These cells had higher levels of XTB protein than the severely affected XP/CS complex patients. An XTB expression vector with the p.F99S mutation partially complemented the NER defect in XP-B cells. The three severely affected XP/CS complex families all have the same splice acceptor site mutation (c.2218-6C > A, p.Q739insX42) in one allele. This resulted in alteration of 41 amino acids at the C terminus, producing partial NER complementation. This limited number of mutations probably reflects the very restricted range of alterations of this vital protein that are compatible with life. We found new mutations in the second allele yielding markedly truncated proteins in all five XT or XP/CS complex families: c.1273C > T, p.R425X; c-471+IG > A, p.K157insTSDSX; C.807-808delTT, p.F270X; c. 1421-1422insA, p.D474EfsX475; and c. 1633C > T, p.Q545X. The remarkable phenotypic heterogeneity of XPB is associated with partially active missense mutations in milder patients while severe XT/CS complex patients have nonsense mutations in both alleles with low levels of altered XTB proteins.