Fanconi anemia (FA) is an autosomal recessively inherited disease with diverse clinical symptoms including developmental anomalies, predisposition to neoplasia, and a deficiency of hematopoietic stem cells resulting in progressive aplastic anemia. FA is genetically heterogeneous with at least 8 genes being implicated on the basis of functional complementation studies. To date, six FA genes are known: FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG, all of which encode orphan proteins sharing no homology to each other nor to any other known protein. In addition, they do not appear to possess any domains with homology to currently known protein domains, which makes a prediction about their molecular action difficult. Studying the molecular evolution of FA genes and their products using sensitive database search methods such as PSI-BLAST may provide novel insight into the nature of the FA pathway and its relationship to hematopoiesis, embryonic development and the origin of malignancies. Preliminary results of such an approach show that at least one FA protein, FANCG, may contain a known domain, suggesting that this protein is a member of the family of tetratricopeptide repeat-containing proteins.

1.
Auerbach AD, Buchwald M, Joenje H: Fanconi Anemia; in Scriver CR, Beadet AL, Valle D, Sly WS, Childs B, Kinzler KW, Vogelstein B (eds): The Metabolic and Molecular Basis of Inherited Disease, ed 8. New York, McGraw-Hill, 2001, pp 753–768.
2.
Joenje H, Patel KJ: The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet 2001;2:446–457.
3.
Sasaki MS, Tonomura A: A high susceptibility of Fanconi’s anemia to chromosome breakage by DNA cross-linking agents. Cancer Res 1973;33:1829–1836.
4.
Auerbach AD, Wolman SR: Susceptibility of Fanconi’s anaemia fibroblasts to chromosome damage by carcinogens. Nature 1976;261:494–496.
5.
Strathdee CA, Duncan AMV, Buchwald M: Evidence for at least four Fanconi anaemia genes including FACC on chromosome 9. Nat Genet 1992;1:196–198.
6.
Joenje H, Oostra AB, Wijker M, di Summa FM, van Berkel CG, Rooimans MA, Ebell, W, van Weel M, Pronk JC, Buchwald M, Arwert F: Evidence for at least eight Fanconi anemia genes. Am J Hum Genet 1997;61:940–944.
7.
Joenje H, Levitus M, Waisfisz Q, D’Andrea A, Garcia-Higuera I, Pearson T, van Berkel CG, Rooimans MA, Morgan N, Mathew CG, Arwert F: Complementation analysis in Fanconi anemia: Assignment of the reference FA-H patient to group A. Am J Hum Genet 2000;67:759–762.
8.
Strathdee CA, Gavish H, Shannon WR, Buchwald M: Cloning of cDNAs for Fanconi’s anemia by functional complementation. Nature 1992;356:763–767.
9.
de Winter JP, Waisfisz Q, Rooimans MA, van Berkel CG, Bosnoyan-Collins L, Alon N, Carreau M, Bender O, Demuth I, Schindler D, Pronk JC, Arwert F, Hoehn H, Digweed M, Buchwald M, Joenje H: The Fanconi anaemia group G gene is identical with XRCC9. Nat Genet 1998;20:281–283.
10.
de Winter JP, Leveille F, van Berkel CG, Rooimans MA, van der Weel L, Steltenpool J, Demuth I, Morgan NV, Alon N, Bosnoyan-Collins L, Lightfoot J, Leegwater PA, Waisfisz Q, Komatsu K, Arwert F, Pronk JC, Mathew CG, Digweed M, Buchwald M, Joenje H: Isolation of a cDNA representing the Fanconi anemia complementation group E gene. Am J Hum Genet 2000;67:1306–1308.
11.
de Winter JP, Rooimans MA, van der Weel L, van Berkel CG, Alon N, Bosnoyan-Collins L, de Groot J, Zhi Y, Waisfisz Q, Pronk JC, Arwert F, Mathew CG, Scheper RJ, Hoatlin ME, Buchwald M, Joenje H: The Fanconi anemia gene FANCF encodes a novel protein with homology to ROM. Nat Genet 2000;24:15–16.
12.
Lo Ten Foe JR, Rooimans MA, Bosnoyan-Collins L, Alon N, Wijker M, Parker L, Lightfoot J, Carreau M, Callen DF, Savoia A, Cheng NC, van Berkel CG, Strunk MH, Gille JJ, Pals G, Kruyt FA, Pronk JC, Arwert F, Buchwald M, Joenje H: Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA. Nat Genet 1996;14:320–323.
13.
The Fanconi Anaemia/Breast Cancer Consortium: Positional cloning of the Fanconi anaemia group A gene. Nat Genet 1996;14:324–328.
14.
Timmers C, Taniguchi T, Hejna J, Reifsteck C, Lucas L, Bruun D, Thayer M, Cox B, Olson S, D’Andrea AD, Moses R, Grompe M: Positional cloning of a novel Fanconi anemia gene, FANCD2. Mol Cell 2001;7:241–248.
15.
Kupfer GM, Naf D, Suliman A, Pulsipher M, D’Andrea AD: The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex. Nat Genet 1997;17:487–490.
16.
Garcia-Higuera I, D’Andrea AD: Regulated binding of the Fanconi anemia proteins FANCA and FANCC. Blood 1999;93:1430–1432.
17.
Waisfisz Q, de Winter JP, Kruyt FA, de Groot J, van der Weel L, Dijkmans LM, Zhi Y, Arwert F, Scheper RJ, Youssoufian H, Hoatlin ME, Joenje H: A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA. Proc Natl Acad Sci USA 1999;96:10320–10325.
18.
de Winter JP, van der Weel L, de Groot J, Stone S, Waisfisz Q, Arwert F, Scheper, RJ, Kruyt FA, Hoatlin ME, Joenje H: The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG. Hum Mol Genet 2000;9:2665–2674.
19.
Yamashita T, Kupfer GM, Naf D, Suliman A, Joenje H, Asano S, D’Andrea AD: The Fanconi anemia pathway requires FAA phosphorylation and FAA/FAC nuclear accumulation. Proc Natl Acad Aci USA 1998;95:13085–13090.
20.
Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D’Andrea AD: Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell 2001;7:249–262.
21.
Li WH, Graur D: Fundamentals of Molecular Evolution. Sunderland, Sinauer, 1991.
22.
Lamb JR, Tugendreich S, Hieter P: Tetratrico peptide repeat interactions: To TPR or not to TPR? Trends Biochem Sci 1995;20:257–259.
23.
Das AK, Cohen PW, Barford D: The structure of the tetratricopeptide repeats of protein phosphatase 5: Implications for TPR-mediated protein-protein interactions. EMBO J 1998;17:1192–1199.
24.
Altschulz SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ: Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Res 1997;25:3389–3402.
25.
Bateman A, Birney E, Durbin R, Eddy SR, Howe KL, Sonnhammer EL: The Pfam protein families database. Nucleic Acids Res 2000;28:263–266.
26.
van de Vrugt HJ, Cheng NC, de Vries Y, Rooimans MA, Groot J, Scheper RJ, Zhi Y, Hoatlin ME, Joenje H, Arwert F: Cloning and characterization of murine Fanconi anemia group A gene: Fanca protein is expressed in lymphoid tissues, testis, and ovary. Mamm Genome 2000;11:326–331.
27.
Wong JC, Alon N, Norga K, Kruyt FA, Youssoufian H, Buchwald M: Cloning and analysis of the mouse Fanconi anemia group A cDNA and an overlapping penta zinc finger cDNA. Genomics 2000;67:273–283.
28.
Wevrick R, Clarke CA, Buchwald M: Cloning and analysis of the murine Fanconi anemia group C cDNA. Hum Mol Genet 1993;2:655–662.
29.
Nakanishi K, Moran A, Hays T, Kuang Y, Fox E, Garneau D, de Oca RM, Grompe M, D’Andrea AD: Functional analysis of patient-derived mutations in the Fanconi anemia gene, FANCG/XRCC9. Exp Hematol 2001;29:842–849.
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