A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.
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 I-like proteins in iron metabolism.
Feder
J N
JN
Mercator Genetics, Inc., Menlo Park, California 94025, USA.
Gnirke
A
A
Thomas
W
W
Tsuchihashi
Z
Z
Ruddy
D A
DA
Basava
A
A
Dormishian
F
F
Domingo
R
R
Ellis
M C
MC
Fullan
A
A
Hinton
L M
LM
Jones
N L
NL
Kimmel
B E
BE
Kronmal
G S
GS
Lauer
P
P
Lee
V K
VK
Loeb
D B
DB
Mapa
F A
FA
McClelland
E
E
Meyer
N C
NC
Mintier
G A
GA
Moeller
N
N
Moore
T
T
Morikang
E
E
Prass
C E
CE
Quintana
L
L
Starnes
S M
SM
Schatzman
R C
RC
Brunke
K J
KJ
Drayna
D T
DT
Risch
N J
NJ
Bacon
B R
BR
Wolff
R K
RK
D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D005075:Biological Evolution; D018244:Chromosomes, Artificial, Yeast; D002896:Chromosomes, Human, Pair 6; D003001:Cloning, Molecular / Q000379:methods; D003545:Cysteine; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression; D005805:Genes, MHC Class I; D005819:Genetic Markers; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D005819:Genetic Markers; C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D012333:RNA, Messenger; D003545:Cysteine