title: Identification of the Fanconi anemia complementation group I gene, FANCI.
abstract: 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.
authors: Department of Clinical Genetics, Vrije Universiteit Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands.
authors: Josephine C
authors: JC
authors: Dorsman
authors: Marieke
authors: M
authors: Levitus
authors: Davy
authors: D
authors: Rockx
authors: Martin A
authors: MA
authors: Rooimans
authors: Anneke B
authors: AB
authors: Oostra
authors: Anneke
authors: A
authors: Haitjema
authors: Sietske T
authors: ST
authors: Bakker
authors: Jûrgen
authors: J
authors: Steltenpool
authors: Dezsö
authors: D
authors: Schuler
authors: Sheila
authors: S
authors: Mohan
authors: Detlev
authors: D
authors: Schindler
authors: Fré
authors: F
authors: Arwert
authors: Gerard
authors: G
authors: Pals
authors: Christopher G
authors: CG
authors: Mathew
authors: Quinten
authors: Q
authors: Waisfisz
authors: Johan P
authors: JP
authors: de Winter
authors: Hans
authors: H
authors: Joenje
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002460:Cell Line; D002648:Child; D043171:Chromosomal Instability / Q000235:genetics; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics*; D005260:Female; D015894:Genome, Human / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C519921:FANCI protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D025801:Ubiquitin