Nature Genetics
14, 320 - 323 (1996)
doi:10.1038/ng1196-320
Expression cloning of a cDNA for the major Fanconi anaemia gene, FAAJerome R. Lo Ten Foe*, 1, Martin A. Rooimans*, 1, Lucine Bosnoyan-Collins*, 2, Noa Alon*, 2, Mario Wijker1, Linda Parker2, Jeff Lightfoot2, Madeleine Carreau2, David F. Callen3, Anna Savoia4, Ngan C. Cheng1, Carola G.M. van Berkel1, Mark H.P. Strunk1, Johan J.P. Gille1, Gerard Pals1, Frank A.E. Kruyt1, Jan C. Pronk1, Fré Arwert1, Manuel Buchwald2
& Hans Joenje1, 5
1Department of Human Genetics, Free University, Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands
2Department of Genetics, The Hospital for Sick Children, 555 University Avenue, and Department of Molecular and Medical Genetics, The University of Toronto, Toronto, Ontario, Canada.
3Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, 72 King William Road, North Adelaide, S.A. 5006, Australia
4Servizio di Genetica Medica, IRCCS - Ospedale CSS, San Giovanni Rotondo, 1-71013, Italy
*J.R.L.T.E, M.A.R., L.B.-C. & N.A. contributed equally to this work
5e-mail: H.Joenje.HumGen@med.vu.nl Fanconi anaemia (FA) is an autosomal recessive disorder characterized by a diversity of clinical symptoms including skeletal abnormalities, progressive bone marrow failure and a marked predisposition to cancer1−4. FA cells exhibit chromosomal instability and hyper-responsiveness to the clastogenic5 and cytotoxic6 effects of bifunctional alkylating (cross-linking) agents, such as diepoxybutane (DEB) and mitomycin C (MMC). Five complementation groups (A−E) have been distinguished on the basis of somatic cell hybridization experiments7−9, with group FA-A accounting for over 65% of the cases analysed10,11. A cDNA for the group C gene (FAC) was reported12 and localized to chromosome 9q22.3 (ref. 8). Genetic map positions were recently reported for two more FA genes, FAA (16q24.3)13 and FAD (3p22−26)14. Here we report the isolation of a cDNA representing the FAA gene, following an expression cloning method similar to the one used to clone the FAC gene12. The 5.5-kb cDNA has an open reading frame of 4,368 nucleotides. In contrast to the 63-kD cytosolic protein encoded by the FAC gene, the predicted FAA protein (Mr 162,752) contains two overlapping bipartite nuclear localization signals and a partial leucine zipper consensus, which are suggestive of a nuclear localization.
REFERENCES
- Giampietro, P.F. et al. The need for more accurate and timely diagnosis in Fanconi anemia. A report from the International Fanconi Anemia Registry. Pediatrics 91, 1116−1120 (1993). | PubMed | ISI | ChemPort |
- Liu, J.M., Buchwald, M., Walsh, C.E. & Young, N.S. Fanconi anemia and novel strategies for therapy. Blood 84, 3995−4007 (1994). | PubMed | ISI | ChemPort |
- Butturini, A., Gale, R.P., Verlander, P.C., Adler-Brecher, B., Gillio, A. & Auerbach, A.D. Hematologic abnormalities in Fanconi anemia. An International Fanconi Anemia Registry study. Blood 84, 1650−1655 (1994). | PubMed | ISI | ChemPort |
- Young, N.S. & Alter, B.P. Aplastic Anemia, Acquired and Inherited. 275−324 (W. B. Saunders, Philadelphia, 1994).
- Auerbach, A.D. Fanconi anemia diagnosis and the diepoxybutane (DEB) test. Exp. Hematol. 21, 731−733 (1993). | PubMed | ISI | ChemPort |
- Kruyt, F.A.E., Dijkmans, L.M., Van den Berg, T.K. & Joenje, H. Fanconi anemia genes act to suppress a crosslinker-inducible p53-independent apoptosis pathway in lymphoblastoid cell lines. Blood 87, 938−948 (1996). | PubMed | ISI | ChemPort |
- Duckworth-Rysiecki, G., Cornish, K., Clarke, C.A. & Buchwald, M. Identification of two complementation groups in Fanconi anemia. Somatic Cell Mol. Genet. 11, 35−41 (1985). | PubMed | ChemPort |
- Strathdee, C.A., Duncan, A.M.V. & Buchwald, M. Evidence for at least four Fanconi anemia genes including FACC on chromosome 9. Nature Genet. 1, 196−198 (1992). | PubMed | ISI | ChemPort |
- Joenje, H. et al. Classification of Fanconi anemia patients by complementation analysis: evidence for a fifth genetic subtype. Blood 86, 2156−2160 (1995). | PubMed | ISI | ChemPort |
- Buchwald, M. Complementation groups: one or more per gene? Nature Genet. 11, 228−230 (1995). | PubMed | ISI | ChemPort |
- Joenje, H. Fanconi anaemia complementation groups in Germany and The Netherlands. Hum. Genet. 97, 280−282 (1996). | PubMed | ISI | ChemPort |
- Strathdee, C.A., Gavish, H., Shannon, W.R. & Buchwald, M. Cloning of Fanconi anemia cDNAs through functional complementation. Nature 356, 763−767 (1992).(Also Nature 358 434). | Article | PubMed | ISI | ChemPort |
- Pronk, J.C. et al. Localisation of the Fanconi anaemia complementation group A gene to chromosome 16q24.3. Nature Genet. 11, 338−340 (1995). | PubMed | ISI | ChemPort |
- Whitney, M. et al. Microcell mediated chromosome transfer maps the Fanconi anemia group D gene to chromosome 3p. Nature Genet. 11, 341−343 (1995). | PubMed | ISI | ChemPort |
- Kneller, D.G., Cohen, F.E. & Langridge, R. Improvements in protein secondary structure prediction by an enhanced neural network. J. Mol. Biol. 214, 171−182 (1990). | PubMed | ISI | ChemPort |
- Bairoch, A. PROSITE: a dictionary of sites and patterns in proteins. Nucl. Acids Res. 19, 2241−2245 (1991). | PubMed | ISI | ChemPort |
- Dingwall, C. & Laskey, R.A. Nuclear targeting sequences — a consensus? Trends Biochem. Sci. 16, 478−481 (1991). | Article | PubMed | ISI | ChemPort |
- Hurst, H.C. Transcription factors. 1: bZIP proteins. Prof. Profile 1, 123−68 (1994). | ChemPort |
- Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403−410 (1990). | Article | PubMed | ISI | ChemPort |
- Friedberg, E.C., Walker, G.C. & Siede, W. DNA Repair and Mutagenesis. 633−685 (ASM, Washington, D.C., 1995).
- Yamashita, T., Barber, D.L., Zhu, Y., Wu, N. & D'Andrea, A.D. Fanconi anemia polypeptide FACC is localized to the cytoplasm. Proc. Natl. Acad. Sci. USA 91, 6712−6716 (1994). | PubMed | ChemPort |
- Youssoufian, H. Localization of Fanconi anemia C protein to the cytoplasm of mammalian cells. Proc. Natl. Acad. Sci. USA 91, 7975−7979 (1994). | PubMed | ChemPort |
- Buchwald, M., Clarke, C., Ng, J., Duckworth-Rysiecki, G. & Weksberg, R. Complementation and gene transfer studies in Fanconi anemia. in Fanconi Anemia, Clinical, Cytogenetic and Experimental Aspects. (eds Schroeder-Kurth T. , Auerbach A.D. & Obe, G.) 226−235 (Springer-Verlag, Berlin, 1989).
- Ishida, R. & Buchwald, M. Susceptibility of Fanconi's anemia lymphoblasts to DNA cross-linking and alkylating agents. Cancer Res. 42, 4000−4006 (1982). | PubMed | ISI | ChemPort |
- Fames, J.A. et al. Submicroscopic deletions at the WAGR locus, revealed by nonradioactive in situ hybridization. Am. J. Hum. Genet. 51, 1286−1294 (1992). | PubMed | ISI | ChemPort |
- Hogervorst, F.B.L. et al. Rapid detection of BRCA1 mutations by the protein truncation test. Nature Genet. 10, 208−212 (1995). | Article | PubMed | ISI | ChemPort |
|
