Human Genetics

, Volume 88, Issue 6, pp 603–607 | Cite as

Molecular basis of group A xeroderma pigmentosum: A missense mutation and two deletions located in a zinc finger consensus sequence of the XPAC gene

  • Ichiro Satokata
  • Kiyoji Tanaka
  • Yoshio Okada
Original Investigations

Summary

The molecular basis of group A xeroderma pigmentosum (XP) was investigated, and 3 mutations located in a zinc finger consensus sequence (nucleotide 313–387) of the XP group A complementing (XPAC) gene were identified in 2 Caucasian patients GM2990 and GM2009 who had typical symptoms of group A XP. The first mutation was a C deletion at nucleotide 374. Patient GM2990 was a homozygote for this mutation. The second mutation was a 5-bp deletion (CTTAT) at nucleotides 349–353. The third mutation was a G to T transversion at nucleotide 323 that alters the Cys-108 codon (TGT) to a Phe codon (TTT). Patient GM2009 was a compound heterozygote for the 5-bp deletion and the missense mutation. Both deletions introduce frameshifts with premature translation terminations resulting in instability of the XPAC mRNA and disruption of the putative zinc finger domain of the XPAC protein. The missense mutation also predicts disruption of the zinc finger domain of the XPAC protein. The expression study showed that the missense mutation does indeed causes loss of repair activity of the XPAC protein. We conclude that these 3 mutations are responsible for group A XP.

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References

  1. Aviv H, Leder P (1972) Purification of biologically active globin messenger RNA by chromatography on oligothymidylic acidcellulose. Proc Natl Acad Sci USA 69:1408–1412Google Scholar
  2. Chirgwin JM, Przybyla AF, MacDonald RJ, Rutter WJ (1979) Isolation of biological active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18:5294–5299Google Scholar
  3. Cleaver JE (1968) Defective repair replication of DNA in xeroderma pigmentosum. Nature 218:652–656Google Scholar
  4. Evans RM, Hollenberg SM (1988) Zinc fingers: gilt by association. Cell 52:1–3Google Scholar
  5. Friedberg EC (1984) DNA Repair. Freeman, New York, pp 505–525Google Scholar
  6. Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp 280–281Google Scholar
  7. Parnes JR, Vean B, Felenfeld A, Ramanathan L, Ferrini U, Appella E, Seidman JG (1981) Mouse β2-microglobulin cDNA clones: a screening procedure for cDNA clones corresponding to rare mRNAs. Proc Natl Acad Sci USA 78:2253–2257Google Scholar
  8. Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA (1988) Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–491Google Scholar
  9. Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467Google Scholar
  10. Satokata I, Tanaka K, Miura N, Miyamoto I, Satoh Y, Kondo S, Okada Y (1990) Characterization of a splicing mutation in group A xeroderma pigmentosum. Proc Natl Acad Sci USA 87:9908–9912Google Scholar
  11. Satokata I, Tanaka K, Miura N, Narita M, Mimaki T, Satoh Y, Kondo S, Okada Y (1992) Three nonsense mutations responsible for group A xeroderma pigmentosum. Mutat Res (in press)Google Scholar
  12. Spritz RA, Forget BD (1983) The thalassemias: molecular mechanisms of human genetic disease. Am J Hum Genet 35:333–361Google Scholar
  13. Tanaka K, Satokata I, Ogita Z, Uchida T, Okada Y (1989) Molecular cloning of a mouse DNA repair gene that complements the defect of group A xeroderma pigmentosum. Proc Natl Acad Sci USA 86:5512–5516Google Scholar
  14. Tanaka K, Miura N, Satokata I, Miyamoto I, Yoshida MC, Satoh Y, Kondo S, Yasui A, Okayama H, Okada Y (1990) Analysis of a human DNA excision repair gene involved in group A xeroderma pigmentosum and a zinc-finger domain. Nature 348:73–76Google Scholar
  15. Wood WI, Gitschier J, Lasky LA, Lawn RM (1985) Base composition-independent hybridization in tetramethylammonium chloride: a method for oligonucleotide screening of highly complex gene libraries. Proc Natl Acad Sci USA 82:1585–1588Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Ichiro Satokata
    • 1
  • Kiyoji Tanaka
    • 1
  • Yoshio Okada
    • 1
  1. 1.Institute for Molecular and Cellular BiologyOsaka UniversityOsakaJapan

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