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Article
Nature Genetics  13, 399 - 408 (1996)
doi:10.1038/ng0896-399

A novel MHC class I−like gene is mutated in patients with hereditary haemochromatosis

J.N. Feder*, 1, A. Gnirke*, 1, W. Thomas*, 1, Z. Tsuchihashi*, 1, D.A. Ruddy1, A. Basava1, F. Dormishian1, R. Domingo Jr.1, M.C. Ellis1, A. Fullan1, L.M. Hinton1, N.L. Jones1, B.E. Kimmel1, G.S. Kronmal1, P. Lauer1, V.K. Lee1, D.B. Loeb1, F.A. Mapa1, E. McClelland1, N.C. Meyer1, G.A. Mintier1, N. Moeller1, T. Moore1, E. Morikang1, C.E. Prass1, L. Quintana1, S.M. Starnes1, R.C. Schatzman1, K.J. Brunke1, D.T. Drayna1, N.J. Risch2, B.R. Bacon3 & R.K. Wolff1, 4

  1Mercator Genetics, Inc., 4040 Campbell Avenue, Menlo Park, California 94025, USA

  2Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA

  3Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, 3635 Vista at Grand Boulevard, St. Louis, Missouri 63110, USA

  *These four authors contributed equally

  4Correspondence should be addressed to R.K.W.

Hereditary haemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi−organ dysfunction caused by increased iron deposition, and is treatable if detected early. Using linkage−disequilibrium and full haplotype analysis, we have identified a 250−kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical−by−descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA−H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class Mike proteins in iron metabolism.

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