Article type: Research Article
Authors: Dorsman, Josephine C.; | Levitus, Marieke | Rockx, Davy | Rooimans, Martin A. | Oostra, Anneke B. | Haitjema, Anneke | Bakker, Sietske T. | Steltenpool, Jûrgen | Schuler, Dezsö | Mohan, Sheila | Schindler, Detlev | Arwert, Fré | Pals, Gerard | Mathew, Christopher G. | Waisfisz, Quinten | de Winter, Johan P. | Joenje, Hans;
Affiliations: Department of Clinical Genetics, Vrije Universiteit Medical Center, Van der Boechorststraat 7, NL-1081 BT Amsterdam, The Netherlands | National Institute of Child Health, Tüzoltó Str. 709, H-1094 Budapest, Hungary | Paediatric Haematology and Oncology, Apollo Specialty Hospital, 320 Padma Complex, Anna Salai, Chennai, 600 035, India | Department of Human Genetics, University of Würzburg, D-97074 Würzburg, Germany | Complex Disease Genetics Group, Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK
Note: [] These authors contributed equally to this work.
Note: [] Present address: Department of Clinical Chemistry, Vrije Universiteit Medical Center, PO Box 7057, NL-1007 MB Amsterdam, The Netherlands.
Note: [] Corresponding author. E-mail: [email protected].
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.
Keywords: Data mining, FANCI, Fanconi anemia, gene identification, positional cloning
Journal: Analytical Cellular Pathology, vol. 29, no. 3, pp. 211-218, 2007
