A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma. (Articolo in rivista)

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  • A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma. (Articolo in rivista) (literal)
Anno
  • 2006-01-01T00:00:00+01:00 (literal)
Alternative label
  • Sidwell RU, Sandison A, Wing J, Fawcett HD, Seet JE, Fisher C, Nardo T, Stefanini M, Lehmann AR, Cream JJ. (2006)
    A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma.
    in British journal of dermatology (1951. Print)
    (literal)
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  • Sidwell RU, Sandison A, Wing J, Fawcett HD, Seet JE, Fisher C, Nardo T, Stefanini M, Lehmann AR, Cream JJ. (literal)
Pagina inizio
  • 81 (literal)
Pagina fine
  • 88 (literal)
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  • 155 (literal)
Rivista
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  • IF (2005) = 2.978 (literal)
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  • Questo lavoro descrive i risultati della caratterizzazione cellulare, genetica e molecolare di una paziente affetta da xeroderma pigmentosum (XP) nella quale un quadro clinico di modesta gravità è risultato inaspettatamente associato a una drastica alterazione nella risposta cellulare alla luce ultravioletta e alla presenza del difetto XP-A. L’analisi molecolare ha evidenziato la presenza in omozigosi di una mutazione mai riportata in precedenza (il cambiamento da A a G dell’ottavo nucleotide al 5’ dell’introne 4) che determina errato processamento del trascritto e produzione di una proteina tronca che non ha attività biologica. Tale mutazione non abolisce però completamente il normale sito donatore di splicing dell’introne 4, permettendo così la produzione una minima quantità di trascritto normale. La presenza di ridotti livelli cellulari di una normale proteina XPA, spiegherebbe sia l’aumentata capacità di compiere sintesi riparativa indotta da UV evidenziata in una frazione di cellule sia l’assenza del quadro clinico grave tipico dei pazienti XP-A, che mostrano in genere precoce comparsa ed elevata frequenza di tumori cutanei e progressiva degenerazione neurologica. (literal)
Note
  • ISI Web of Science (WOS) (literal)
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  • Sidwell, Cream: Dept. of Dermatology, Charing Cross Hospital, London, UK; Sandison, Seet: Dept. of Histopathology, Charing Cross Hospital, London, UK; Wing, Fawcett, Lehmann: Genome Damage and Stability Centre, University of Sussex, Brighton, UK; Fisher: Dept. of Histopathology, Royal Marsden Hospital, London, UK; Nardo, Stefanini: IGM CNR, Pavia, Italy (literal)
Titolo
  • A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma. (literal)
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. OBJECTIVES: 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. (literal)
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