HLA-H Mutations in the Ashkenazi Jewish Population

doi:10.1006/bcmd.1997.0125

Blood Cells, Molecules, and Diseases

Volume 23, Issue 1, April 1997, Pages 95-98

https://doi.org/10.1006/bcmd.1997.0125 Get rights and content

Abstract

ABSTRACT: Hereditary hemochromatosis is a common disorder in people of European origin. The HLA-H gene has been found to have two mutations that apparently cause hemochromatosis. The principal mutation, 845G→A (C282Y), is believed to have arisen relatively recently in the Celtic population. To determine the incidence of this mutation and the other hemochromatosis-associated mutation, 187C→G (H63D), among Ashkenazi Jews, a people who are believed to have arrived in Europe in about the 8^thCentury A.D., we have examined the DNA from 381 unrelated Jewish subjects and 206 non-Jewish white controls. The gene frequency for the 845G→A mutation among Jewish subjects was only 0.013 compared with a frequency of 0.070 among controls, a difference that is significant at the 0.00001 level. The phenotypically milder nt 187C→G mutation had a frequency of 0.155 in the non-Jewish population and 0.097 in the Jewish population, a difference that was also statistically significant at the <0.01 level.

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Cited by (41)

Ferritinemia during type 1 Gaucher disease: Mechanisms and progression under treatment
2012, Blood Cells, Molecules, and Diseases
Citation Excerpt :
To the best of our knowledge, no previous study examined possible causes of hyperferritinemia in GD. Moreover, even though the hereditary hemochromatosis C282Y and H63D mutations are rare in type-1 GD populations, no investigation included an analysis of their frequencies in the context of hyperferritinemia, except Stein et al., but overall frequencies were not exported in this paper [6–8]. When hyperferritinemia is present, TSC > 60% should initially evoke hereditary hemochromatosis, whereas a 45–60% TSC suggests other possible diseases responsible for iron overload.
Earlier results highlighted hyperferritinemia during type-1 Gaucher disease (GD), but its potential mechanisms and long-term progression remained unexamined.
We analyzed the clinical, biological and iron characteristics of type-1 GD patients, before and after starting enzyme-replacement therapy (ERT). Iron parameters under ERT were subjected to linear-regression analyses.
Serum ferritin (median 739 [46–2371] μg/L) was determined for 54 patients (21 (39%) males; median age 32 [range 12–73] years) before ERT; it exceeded 300 μg/L in 47 (87%), while the other iron parameters always remained normal: transferrin saturation coefficient (26 [16–42]), serum iron at 13 [6–22] mmol/L and transferrin at 2.4 [2,3] g/L. Four patients had mild elevation of liver transaminases, with C-reactive protein > 20 mg/l in two. The absence of hemolysis was accompanied by a median bilirubin of 9 μmol/L and lactate dehydrogenase at 250 IU/L; diabetes and lipid anomalies were not observed. Clinical, biological and iron parameters at GD diagnosis were comparable for the 12 and 42 patients with ferritinemia ≤ 400 and > 400 μg/L, respectively. Ferritinemia was measured at least once for 46 patients after ERT onset (median treatment duration 90 [3–204] months). At study closure, median serum ferritin was 187.5 [11–1560] μg/L, exceeding 300 μg/L in 15 (33%) patients, while the other iron parameters were normal. Among the latter, only the mean ± SD ferritinemia slope decreased significantly under ERT (− 1.9 ± 0.3%/month; p < 0.001).
Hyperferritinemia is a specific GD characteristic and serum ferritin monitoring could be informative during follow-up.
Frequencies of C282Y and H63D alleles in the HFE gene among various Jewish ethnic groups in Israel: A change of concept required
2010, Genetics in Medicine
Hereditary hemochromatosis has not been fully evaluated in the non-Ashkenazi population and is considered to be relatively rare. After ascertaining three unrelated hereditary hemochromatosis families of North African Jewish origin with the HFE C282Y/C282Y genotype, we evaluated the C282Y and H63D allele frequencies among the different Jewish ethnic groups in Israel, in particular North African Jews.
Data were collected from three Israeli Medical Centers. North African, Oriental, Yemenite, and Sephardic Jewish healthy individuals were assessed for the C282Y and H63D alleles.
The C282Y allele frequency was 1.02% (6/586 chromosomes), and the H63D allele frequency was 13.82% (81/586 chromosomes) in the North African Jewish group. The C282Y allele was not detected in the other non-Ashkenazi groups. The H63D allele frequency was 12.5% (38/304 chromosomes) in Oriental Jews, 14.9% (14/94 chromosomes) in Yemenite Jews, and 9.3% (11/118 chromosomes) in Sephardic Jews.
Hereditary hemochromatosis is underrecognized among North African Jews, who have carrier frequencies of 1/58 and 1/4 for C282Y and H63D, respectively. HFE-hereditary hemochromatosis is not rare among this population as currently thought and merits increased awareness to prevent endpoint disease. The frequent occurrence of β-thalassemia trait and HFE-H63D in non-Ashkenazi Jews raises the possibility of genetic interactions contributing to iron overload when coinherited and requires further evaluation.
Molecular basis in hereditary haemochromatosis
2005, Revue de Medecine Interne
Propos. – Les bases moléculaires à l’origine d’un phénotype de surcharge en fer héréditaire sont désormais mieux connues et conduisent à établir une nouvelle classification des hémochromatoses génétiques que nous présentons dans cette mise au point.
Actualités et points forts. – La forme principale d’hémochromatose génétique est liée au gène HFE au sein duquel une mutation (C282Y) est observée chez la plupart des malades. Récemment, plusieurs autres gènes codant des protéines impliquées dans le métabolisme du fer (ferroportine, RTF2, hepcidine, hémojuvéline) ont été découverts. Des mutations dans ces différents gènes sont responsables de surcharges en fer primaires. Des données nouvelles nous permettent de conclure aux notions d’hétérogénéité génétique et allélique des hémochromatoses et de proposer l’existence d’un mode de transmission digénique de certaines d’entre elles.
Perspectives et projets. – Il reste en perspective la découverte de nouveaux facteurs modificateurs, modulateurs ou aggravants, des phénotypes morbides. Certains d’entre eux pourraient expliquer la pénétrance incomplète du génotype C282Y homozygote.
Purpose. – Recent discoveries in molecular mechanisms of iron metabolism have changed the classical view of hereditary iron overload conditions. We present natural mutations in newly discovered genes and related phenotypes observed in patients with different form of haemochromatosis.
Current knowledge and key points. – Most haemochromatosis patients are homozygous for the C282Y mutation in the HFE gene. Ferroportin, TFR2, hemojuvelin and hepcidin mutations also cause iron overload. Recent data support the hypothesis that haemochromatosis should no longer be considered a monogenic disease but rather an oligogenic disorder. Several results suggest that haemochromatosis could result from digenic inheritance of mutations in HFE and HAMP.
Future prospects and projects. – Other modifier genes probably influence penetrance in C282Y homozygous patients. Such genes could enhance or reduce the phenotypic expression in various iron overload conditions.
The roles of iron in health and disease
2001, Molecular Aspects of Medicine
Iron is vital for almost all living organisms by participating in a wide variety of metabolic processes, including oxygen transport, DNA synthesis, and electron transport. However, iron concentrations in body tissues must be tightly regulated because excessive iron leads to tissue damage, as a result of formation of free radicals. Disorders of iron metabolism are among the most common diseases of humans and encompass a broad spectrum of diseases with diverse clinical manifestations, ranging from anemia to iron overload and, possibly, to neurodegenerative diseases. The molecular understanding of iron regulation in the body is critical in identifying the underlying causes for each disease and in providing proper diagnosis and treatments. Recent advances in genetics, molecular biology and biochemistry of iron metabolism have assisted in elucidating the molecular mechanisms of iron homeostasis. The coordinate control of iron uptake and storage is tightly regulated by the feedback system of iron responsive element-containing gene products and iron regulatory proteins that modulate the expression levels of the genes involved in iron metabolism. Recent identification and characterization of the hemochromatosis protein HFE, the iron importer Nramp2, the iron exporter ferroportin1, and the second transferrin-binding and -transport protein transferrin receptor 2, have demonstrated their important roles in maintaining body's iron homeostasis. Functional studies of these gene products have expanded our knowledge at the molecular level about the pathways of iron metabolism and have provided valuable insight into the defects of iron metabolism disorders. In addition, a variety of animal models have implemented the identification of many genetic defects that lead to abnormal iron homeostasis and have provided crucial clinical information about the pathophysiology of iron disorders. In this review, we discuss the latest progress in studies of iron metabolism and our current understanding of the molecular mechanisms of iron absorption, transport, utilization, and storage. Finally, we will discuss the clinical presentations of iron metabolism disorders, including secondary iron disorders that are either associated with or the result of abnormal iron accumulation.
Screening for hemochromatosis: A public health perspective
1999, American Journal of Preventive Medicine
Context: The discovery of the HFE gene in 1996 has introduced DNA testing as a possible tool for screening and diagnosis of hemochromatosis and increased interest in the disorder. Population screening using transferrin saturation has been advocated by experts to permit early detection and treatment with phlebotomy before the onset of clinical disease.
Methods: Based on a literature review, we consider the relative risks and merits of two screening tests as part of a broader look at the evidence required for the recommendation of universal screening for hemochromatosis.
Results: Several questions must be answered before universal screening can be recommended. Uncertainties remain about the penetrance and preventable disease burden, laboratory standardization, and optimal strategies to minimize potential risks of screening for hemochromatosis.
Conclusions: As a common genetic disorder with simple, effective therapy, hemochromatosis offers a model for other genetically influenced chronic diseases that some day may have interventions to improve prognosis. Resolution of questions related to prevention of chronic diseases from hemochromatosis, therefore, will have broad usefulness in the future.
Hemochromatosis mutations are not linked to dilated cardiomyopathy in Israeli patients
2004, European Journal of Heart Failure

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^☆: 03/26/97

^☆☆: R, M, GoodmanA, G, Motulsky, eds.

^f1: Reprint request to: Ernest Beutler, M.D., The Scripps Research Institute, Department of Molecular and Experimental Medicine, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA, phone (619)784-8040, fax (619)784-2083, e-mail: [email protected]

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Regular ArticleHLA-H Mutations in the Ashkenazi Jewish Population☆,☆☆

Abstract

Blood Cells Mol Dis

Blood

A novel MHC class I-like gene is mutated in patients with hereditary haemachromatosis

Nature Genet

Haemochromatosis and HLA-H

Nature Genet

Haplotype analysis in Australian hemochromatosis patients: Evidence for a predominant ancestral haplotype exclusively associated with hemochromatosis

Am J Hum Genet

Prevalence of idiopathic hemochromatosis in Italy: Study of 1301 blood donors

Haematologica (Pavia)

Regular Article
HLA-H Mutations in the Ashkenazi Jewish Population☆,☆☆