title: A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma.
abstract: BACKGROUND
  Xeroderma pigmentosum (XP) is an autosomal recessive disorder of, in most cases, defective nucleotide excision repair (NER) of ultraviolet radiation (UV)- and chemical-induced DNA damage. The condition is characterized by an increased sensitivity of the skin to UV radiation, with early development of pigmentary changes and premalignant lesions in sun-exposed areas of the skin, signs of photoageing and a greatly increased incidence from a young age of skin tumours including melanoma. Approximately 20% of patients with XP show neurological abnormalities of varying severity due to primary neuronal degeneration. Genetic analysis by somatic cell hybridization has led to the identification in the NER-defective form of XP of seven complementation groups, designated XP-A to XP-G. These complementation groups correspond to different proteins involved in the NER process. XP-A classically includes some of the most severely affected patients.
  
  
  OBJECTIVE
  We describe a 61-year-old Punjabi woman with XP. Remarkably she had only mild cutaneous abnormalities, minimal neurological features and unusual longevity, and developed a malignant spindle cell melanoma. There are few previous reports of spindle cell melanoma associated with XP. To gain insight into the aetiology of these unusual features, we sought to analyse the DNA repair properties of the patient and identify the complementation group and the causative mutation in the defective gene.
  
  
  METHODS
  Unscheduled DNA synthesis and the inhibition of RNA synthesis were measured. The complementation group was assigned by fusing the cells of our patient with XP cells of known complementation groups and determining the ability to carry out unscheduled DNA repair. Molecular analysis of the cDNA was carried out by polymerase chain reaction and DNA sequencing.
  
  
  RESULTS
  Levels of DNA repair were extremely low and complementation analysis assigned the defect to the XP-A group. Sequencing of the XPA gene revealed a novel homozygous mutation of A-->G at the eighth nucleotide of intron 4 causing aberrant splicing and a nonfunctional truncated XP-A protein. However, a small amount of normally spliced mRNA was detected at <5% the level in normal cells.
  
  
  CONCLUSIONS
  The small amount of normally spliced mRNA detected may be sufficient to explain the relatively mild clinical features in our patient.
authors.affiliation: Department of Dermatology, Charing Cross Hospital, London, and Genome Damage and Stability Centre, University of Sussex, Brighton, UK.
authors.forename: R U
authors.initials: RU
authors.lastname: Sidwell
authors.forename: A
authors.initials: A
authors.lastname: Sandison
authors.forename: J
authors.initials: J
authors.lastname: Wing
authors.forename: H D
authors.initials: HD
authors.lastname: Fawcett
authors.forename: J-E
authors.initials: JE
authors.lastname: Seet
authors.forename: C
authors.initials: C
authors.lastname: Fisher
authors.forename: T
authors.initials: T
authors.lastname: Nardo
authors.forename: M
authors.initials: M
authors.lastname: Stefanini
authors.forename: A R
authors.initials: AR
authors.lastname: Lehmann
authors.forename: J J
authors.initials: JJ
authors.lastname: Cream
mesh_terms: D000346:Afghanistan / Q000208:ethnology; D004260:DNA Repair; D005260:Female; D005816:Genetic Complementation Test; D006720:Homozygote; D006801:Humans; D008131:London; D008545:Melanoma / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D014983:Xeroderma Pigmentosum / Q000150:complications / Q000235:genetics / Q000473:pathology; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics*
chemical_list: D051760:Xeroderma Pigmentosum Group A Protein