Identification of the Fanconi Anemia Complementation Group I Gene, FANCI

• Main Authors: Josephine C. Dorsman, Marieke Levitus, Davy Rockx, Martin A. Rooimans, Anneke B. Oostra, Anneke Haitjema, Sietske T. Bakker, Jûrgen Steltenpool, Dezsö Schuler, Sheila Mohan, Detlev Schindler, Fré Arwert, Gerard Pals, Christopher G. Mathew, Quinten Waisfisz, Johan P. de Winter, Hans Joenje
• Format: Article
• Language: English
• Published: Hindawi Limited 2007-01-01
• Series: Cellular Oncology
• Online Access: http://dx.doi.org/10.1155/2007/151968

To identify the gene underlying Fanconi anemia (FA) complementation group I we studied informative FA-I families by a genome-wide linkage analysis, which resulted in 4 candidate regions together encompassing 351 genes. Candidates were selected via bioinformatics and data mining on the basis of their resemblance to other FA genes/proteins acting in the FA pathway, such as: degree of evolutionary conservation, presence of nuclear localization signals and pattern of tissue-dependent expression. We found a candidate, KIAA1794 on chromosome 15q25-26, to be mutated in 8 affected individuals previously assigned to complementation group I. Western blots of endogenous FANCI indicated that functionally active KIAA1794 protein is lacking in FA-I individuals. Knock-down of KIAA1794 expression by siRNA in HeLa cells caused excessive chromosomal breakage induced by mitomycin C, a hallmark of FA cells. Furthermore, phenotypic reversion of a patient-derived cell line was associated with a secondary genetic alteration at the KIAA1794 locus. These data add up to two conclusions. First, KIAA1794 is a FA gene. Second, this gene is identical to FANCI, since the patient cell lines found mutated in this study included the reference cell line for group I, EUFA592.