TY - JOUR
T1 - Heterogeneity in Fanconi anemia
T2 - Evidence for 2 new genetic subtypes
AU - Levitus, Marieke
AU - Rooimans, Martin A.
AU - Steltenpool, Jûrgen
AU - Cool, Nicolle F.C.
AU - Oostra, Anneke B.
AU - Mathew, Christopher G.
AU - Hoatlin, Maureen E.
AU - Waisfisz, Quinten
AU - Arwert, Fré
AU - De Winter, Johan P.
AU - Joenje, Hans
PY - 2004/4/1
Y1 - 2004/4/1
N2 - 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.
AB - 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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U2 - 10.1182/blood-2003-08-2915
DO - 10.1182/blood-2003-08-2915
M3 - Article
C2 - 14630800
AN - SCOPUS:12144288675
SN - 0006-4971
VL - 103
SP - 2498
EP - 2503
JO - Blood
JF - Blood
IS - 7
ER -