Heterogeneity in Fanconi anemia: evidence for 2 new genetic subtypes

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, 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.