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Phenotypic Heterogeneity in the XPB DNA Helicase Gene (ERCC3): Xeroderma Pigmentosum Without and With Cockayne Syndrome

journal contribution
posted on 2023-06-07, 13:52 authored by Kyu-Seon Oh, Sikandar G. Khan, N.G.J. Jaspers, Anja Raams, Takahiro Ueda, Alan LehmannAlan Lehmann, Peter S. Friedmann, Steffen Emmert, Alexi Gratchev, Katherine Lachlan, Anneke Lucassan, Carl C. Baker, Kenneth H. Kraemer
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 (XP) 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 XPB protein than the severely affected XP/CS complex patients. An XPB 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 XP or XP/CS complex families: c.1273C>T, p.R425X; c.471+1G>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 XP/CS complex patients have nonsense mutations in both alleles with low levels of altered XPB proteins.

History

Publication status

  • Published

Journal

Human Mutation

ISSN

1059-7794

Publisher

Wiley-Blackwell

Issue

11

Volume

27

Page range

1092-1103

Notes

GDSC198

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2007-03-16

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