Heterogeneity in Fanconi anemia: Evidence for 2 new genetic subtypes

Marieke Levitus, Martin A. Rooimans, Jûrgen Steltenpool, Nicolle F C Cool, Anneke B. Oostra, Christopher G. Mathew, Maureen Hoatlin, Quinten Waisfisz, Fré Arwert, Johan P. De Winter, Hans Joenje

Research output: Contribution to journalArticle

190 Citations (Scopus)

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 subtypes have been described for FA (A, B, C, Dl, 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.

Original languageEnglish (US)
Pages (from-to)2498-2503
Number of pages6
JournalBlood
Volume103
Issue number7
DOIs
StatePublished - Apr 1 2004
Externally publishedYes

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Fanconi Anemia
Genes
Cells
Fanconi Anemia Complementation Group D2 Protein
Defects
Bone
Stabilization
Chemical activation
Cell Line
Multiprotein Complexes
Hybrid Cells
Ubiquitination
Acute Myeloid Leukemia

ASJC Scopus subject areas

  • Hematology

Cite this

Levitus, M., Rooimans, M. A., Steltenpool, J., Cool, N. F. C., Oostra, A. B., Mathew, C. G., ... Joenje, H. (2004). Heterogeneity in Fanconi anemia: Evidence for 2 new genetic subtypes. Blood, 103(7), 2498-2503. https://doi.org/10.1182/blood-2003-08-2915

Heterogeneity in Fanconi anemia : Evidence for 2 new genetic subtypes. / Levitus, Marieke; Rooimans, Martin A.; Steltenpool, Jûrgen; Cool, Nicolle F C; Oostra, Anneke B.; Mathew, Christopher G.; Hoatlin, Maureen; Waisfisz, Quinten; Arwert, Fré; De Winter, Johan P.; Joenje, Hans.

In: Blood, Vol. 103, No. 7, 01.04.2004, p. 2498-2503.

Research output: Contribution to journalArticle

Levitus, M, Rooimans, MA, Steltenpool, J, Cool, NFC, Oostra, AB, Mathew, CG, Hoatlin, M, Waisfisz, Q, Arwert, F, De Winter, JP & Joenje, H 2004, 'Heterogeneity in Fanconi anemia: Evidence for 2 new genetic subtypes', Blood, vol. 103, no. 7, pp. 2498-2503. https://doi.org/10.1182/blood-2003-08-2915
Levitus M, Rooimans MA, Steltenpool J, Cool NFC, Oostra AB, Mathew CG et al. Heterogeneity in Fanconi anemia: Evidence for 2 new genetic subtypes. Blood. 2004 Apr 1;103(7):2498-2503. https://doi.org/10.1182/blood-2003-08-2915
Levitus, Marieke ; Rooimans, Martin A. ; Steltenpool, Jûrgen ; Cool, Nicolle F C ; Oostra, Anneke B. ; Mathew, Christopher G. ; Hoatlin, Maureen ; Waisfisz, Quinten ; Arwert, Fré ; De Winter, Johan P. ; Joenje, Hans. / Heterogeneity in Fanconi anemia : Evidence for 2 new genetic subtypes. In: Blood. 2004 ; Vol. 103, No. 7. pp. 2498-2503.
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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 subtypes have been described for FA (A, B, C, Dl, 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.",
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