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| Heterogeneity in Fanconi anemia: evidence for 2 new genetic subtypes |
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| Author(s): Levitus M, Rooimans MA, Steltenpool J, Cool NFC, Oostra AB, Mathew CG, Hoatlin ME, Waisfisz Q, Arwert F, de Winter JP, Joenje H |
| Source: BLOOD Volume: 103 Issue: 7 Pages: 2498-2503 Published: APR 1 2004 |
| Times Cited: 121 References: 25 |
| Abstract: Fanconi anemia (FA) is an autosomal recessive syndrome featuring diverse symptoms including progressive bone marrow failure and early occurrence of acute myeloid leukemia. Nine genetic sub-types have been described for FA (A, B, C, D1, D2, E, F, G, and L), all of which have been connected to distinct disease genes, except B. Here we report on 8 unrelated FA patients who were excluded from the known subtypes on the basis of phenotypic correction or genetic data. Four of these cell lines failed to complement each other in somatic cell hybrids and therefore represent a new group, termed FA-I. The remaining cell lines complemented group FA-I but did not complement each other, thus representing a second new group, FA-J. Both FA-I and -J cell lines were capable of forming an FA multiprotein core complex. This complex is required for activation of the FANCD2 protein by mono-ubiquitination, a key downstream event in the FA pathway. In FA-I cells FANCD2 was not mono-ubiquitinated, indicating a defect upstream in the FA pathway, whereas in FA-J cells FANCD2 was mono-ubiquitinated, indicating a downstream defect. Our results suggest that the FA pathway of genome stabilization may be controlled by at least 11 different genes, including FANCI and FANCJ. (C) 2004 by The American Society of Hematology. |
| Document Type: Article |
| Language: English |
| Reprint Address: Joenje, H (reprint author), VU Univ, Med Ctr, Dept Clin Genet & Human Genet, Van Boechorstr 7, NL-1081 BT Amsterdam, Netherlands |
Addresses:
1. VU Univ, Med Ctr, Dept Clin Genet & Human Genet, NL-1081 BT Amsterdam, Netherlands
2. Guys Hosp, GKT Sch Med, Div Genet & Dev, London SE1 9RT, England
3. Div Mol Med & Mol & Med Genet, Portland, OR USA |
| Publisher: AMER SOC HEMATOLOGY, 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA |
| Subject Category: Hematology |
| IDS Number: 830ZR |
| ISSN: 0006-4971 |
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