These authors are considered as the joint first coauthors.
Correlation of Phenotype/Genotype in a Cohort of 23 Xeroderma Pigmentosum-Variant Patients Reveals 12 New Disease-Causing POLH Mutations
Article first published online: 4 NOV 2013
© 2013 WILEY PERIODICALS, INC.
Volume 35, Issue 1, pages 117–128, January 2014
How to Cite
Opletalova, K., Bourillon, A., Yang, W., Pouvelle, C., Armier, J., Despras, E., Martin, L., Mateus, C., Robert, C., Kannouche, P., Soufir, N. and Sarasin, A. (2014), Correlation of Phenotype/Genotype in a Cohort of 23 Xeroderma Pigmentosum-Variant Patients Reveals 12 New Disease-Causing POLH Mutations. Hum. Mutat., 35: 117–128. doi: 10.1002/humu.22462
Contract grant sponsors: Centre National de la Recherche Scientifique (Paris, France); the Agence Nationale pour la Recherche (Paris); the Association des Enfants de la Lune (Tercis, France); La Ligue Nationale contre le Cancer (“Equipe labellisée”), Paris, France; the Institut National du Cancer (INCa, PLBio-2010), Paris; the Agence Nationale de la Recherche (N° ANR-09-PIRI-001), Paris.
Communicated by Rolf H. Sijmons
- Issue published online: 18 DEC 2013
- Article first published online: 4 NOV 2013
- Accepted manuscript online: 15 OCT 2013 10:35AM EST
- Manuscript Accepted: 2 OCT 2013
- Manuscript Received: 11 JUL 2013
- Centre National de la Recherche Scientifique (Paris, France)
- Agence Nationale pour la Recherche (Paris)
- Association des Enfants de la Lune (Tercis, France)
- La Ligue Nationale contre le Cancer (“Equipe labellisée”), Paris, France
- Institut National du Cancer. Grant Number: INCa, PLBio-2010
- Agence Nationale de la Recherche. Grant Number: N° ANR-09-PIRI-001
- DNA repair;
- trans-lesion polymerases;
- skin cancers;
Xeroderma pigmentosum variant (XP-V) is a rare genetic disease, characterized by some sunlight sensitivity and predisposition to cutaneous malignancies. We described clinical and genetic features of the largest collection ever published of 23 XP-V patients (ages between 21 and 86) from 20 unrelated families. Primary fibroblasts from patients showed normal nucleotide excision repair but UV-hypersensitivity in the presence of caffeine, a signature of the XP-V syndrome. 87% of patients developed skin tumors with a median age of 21 for the first occurrence. The median numbers of basal-cell carcinoma was 13 per patient, six for squamous-cell carcinoma, and five for melanoma. XP-V is due to defects in the translesion-synthesis DNA polymerase Polη coded by the POLH gene. DNA sequencing of POLH revealed 29 mutations, where 12 have not been previously identified, leading to truncated polymerases in 69% of patients. Four missense mutations are correlated with the protein stability by structural modeling of the Polη polymerase domain. There is a clear relationship between the types of missense mutations and clinical severity. For truncating mutations, which lead to an absence of or to inactive proteins, the life-cumulated UV exposure is probably the best predictor of cancer incidence, reinforcing the necessity to protect XP-Vs from sun exposure.