Research Article

Distribution of mutations in the human xeroderma pigmentosum group A gene and their relationships to the functional regions of the DNA damage recognition protein

  1. JC States1,2,
  2. ER McDuffie1,
  3. SP Myrand1,2,
  4. M McDowell3,
  5. JE Cleaver3,*

Article first published online: 7 DEC 1999

DOI: 10.1002/(SICI)1098-1004(1998)12:2<103::AID-HUMU5>3.0.CO;2-6

Issue

Human Mutation

Human Mutation

Volume 12, Issue 2, pages 103–113, 1998

Additional Information

How to Cite

States, J., McDuffie, E., Myrand, S., McDowell, M. and Cleaver, J. (1998), Distribution of mutations in the human xeroderma pigmentosum group A gene and their relationships to the functional regions of the DNA damage recognition protein. Human Mutation, 12: 103–113. doi: 10.1002/(SICI)1098-1004(1998)12:2<103::AID-HUMU5>3.0.CO;2-6

Author Information

  1. 1

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI

  2. 2

    Institute of Chemical Toxicology, Wayne State University, Detroit, MI

  3. 3

    Department of Dermatology and Laboratory of Radiobiology and Environmental Health, University of California, San Francisco, CA

*Department of Dermatology and Laboratory of Radiobiology and Environmental Health, University of California, San Francisco, CA 94143-0750

Publication History

  1. Issue published online: 7 DEC 1999
  2. Article first published online: 7 DEC 1999
  3. Manuscript Accepted: 14 APR 1998
  4. Manuscript Received: 3 OCT 1997

Funded by

  • March of Dimes Birth Defects Foundation. Grant Numbers: 6-FY95-0338, 6-FY95-1032
  • Cancer Research Coordinating Committee and the Academic Senate Committee on Research of the University of California, San Francisco
  • National Center for Resources (NIH). Grant Numbers: S03 RR03332, P30 ES06639, R01 ES06460

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Keywords:

  • xeroderma pigmentosum;
  • XPA;
  • mutation slicing;
  • single strand conformation polymorphism;
  • DNA repair

Abstract

A series of xeroderma pigmentosum group A cell lines from 19 patients and cell lines from 13 other family members were examined for XPA mutations to find previously unidentified mutations from American and European patients, to establish pedigrees in represented families, and to develop a database for XPA diagnosis. Most mutations were deletions and splice site mutations observed previously in other XPA patients, in exon III, intron III, or exon IV, that resulted in frameshifts within the DNA binding region—including an Afl III RFLP (G to C) in four unrelated families. One new mutation was a point mutation within intron III (A to G) creating a new splice acceptor site that may compete with the original splice acceptor site. Missplicing at this new site inserts 11 nucleotides in the mRNA creating a frameshift. A small amount of normal splicing to give wild-type XPA protein is the likely molecular mechanism for the relatively mild clinical features of this patient. In another patient, a new 2 bp deletion in the RPA70 binding region was identified in the same region was identified in the same region as a 20 bp deletion previously characterized in an unrelated patient. Mutations in the DNA binding region of XPA were from patients with the more severe disease often associated with neurological complications, whereas mutations in the C-terminal end of the protein, which interacts with the TFIIH transcription factor, were from patients with milder skin disease only. The rarity of naturally occurring missense mutations in the DNA binding region of XPA suggests that amino acid changes might be sufficiently tolerated that patients would have mild symptoms and escape detection. Hum Mutat 12:103–113, 1998. © 1998 Wiley-Liss, Inc.

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