Mutation analysis in hereditary hemochromatosis

Ernest Beutler, Terri Gelbart, Carol West, Pauline Lee, Michele Adams, Ryan Blackstone, Paul Pockros, Michael Kosty, Charles P. Venditti, Pradyumna D. Phatak, Nicole K. Seese, Karen A. Chorney, Amy E. Ten Elshof, Glenn S. Gerhard, Michael J. Chorney

Research output: Contribution to journalArticle

358 Citations (Scopus)

Abstract

The DNA of 147 patients of European origin clinically diagnosed with idiopathic hemochromatosis and 193 controls was examined for mutations of the HLA-H gene at nt 845 and nt 187. One hundred twenty-one (82.3%) of the hemochromatosis patients were homozygous and 10 (6.8%) heterozygous for the 845A (C282Y) mutation. All of the homozygous patients were also homozygous for nt 187C, and all 845A heterozygotes had at least one copy of 187C. Thus, the nt 845 and nt 187 mutations were in complete linkage disequilibrium; nt 187 was a C on all chromosomes with the 845A mutation. Eight of the 10 heterozygotes for 845A were heterozygous for 187G(H63D). The excess of heterozygotes at both nt 187 and nt 845 suggested either the presence of as yet undiscovered mutations existing in trans with 845A and in linkage disequilibrium with 187G, or that the 187G itself is a deleterious mutation, which in concert with the 845A can give rise to hemochromatosis. None of the 193 normal controls were homozygous for 845A and 29/193 (15%) were heterozygous for 845A. Although 47/193 (24.3%) of normal controls were heterozygous for the 187G mutation only two of these carried the 845A mutation. If the 187G mutation complemented the 845A mutation with high penetrance in causing hemochromatosis, then the population frequency of the two genes would require that a high proportion of patients with hemochromatosis be heterozygous for 845A and 187G. Instead, the frequency of homozygotes for the 845A mutation was much higher than that of the 845A/187G genotype. Based on our data, the penetrance of the 845A/187G genotype is only 1.5% and based on the data of Feder et al. only 0.5%. In contrast, the penetrance of the homozygous 845A/845A genotype seems to be very high. Thus, screening for this genotype should be very useful.

Original languageEnglish (US)
Pages (from-to)187-194
Number of pages8
JournalBlood Cells, Molecules, and Diseases
Volume22
Issue number2
DOIs
StatePublished - Jan 1 1996

Fingerprint

Hemochromatosis
Mutation
Penetrance
Heterozygote
Genotype
Linkage Disequilibrium
Homozygote
Gene Frequency
Chromosomes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Hematology
  • Cell Biology

Cite this

Beutler, E., Gelbart, T., West, C., Lee, P., Adams, M., Blackstone, R., ... Chorney, M. J. (1996). Mutation analysis in hereditary hemochromatosis. Blood Cells, Molecules, and Diseases, 22(2), 187-194. https://doi.org/10.1006/bcmd.1996.0027
Beutler, Ernest ; Gelbart, Terri ; West, Carol ; Lee, Pauline ; Adams, Michele ; Blackstone, Ryan ; Pockros, Paul ; Kosty, Michael ; Venditti, Charles P. ; Phatak, Pradyumna D. ; Seese, Nicole K. ; Chorney, Karen A. ; Ten Elshof, Amy E. ; Gerhard, Glenn S. ; Chorney, Michael J. / Mutation analysis in hereditary hemochromatosis. In: Blood Cells, Molecules, and Diseases. 1996 ; Vol. 22, No. 2. pp. 187-194.
@article{f0ab0a601749492bb8756321be4ad638,
title = "Mutation analysis in hereditary hemochromatosis",
abstract = "The DNA of 147 patients of European origin clinically diagnosed with idiopathic hemochromatosis and 193 controls was examined for mutations of the HLA-H gene at nt 845 and nt 187. One hundred twenty-one (82.3{\%}) of the hemochromatosis patients were homozygous and 10 (6.8{\%}) heterozygous for the 845A (C282Y) mutation. All of the homozygous patients were also homozygous for nt 187C, and all 845A heterozygotes had at least one copy of 187C. Thus, the nt 845 and nt 187 mutations were in complete linkage disequilibrium; nt 187 was a C on all chromosomes with the 845A mutation. Eight of the 10 heterozygotes for 845A were heterozygous for 187G(H63D). The excess of heterozygotes at both nt 187 and nt 845 suggested either the presence of as yet undiscovered mutations existing in trans with 845A and in linkage disequilibrium with 187G, or that the 187G itself is a deleterious mutation, which in concert with the 845A can give rise to hemochromatosis. None of the 193 normal controls were homozygous for 845A and 29/193 (15{\%}) were heterozygous for 845A. Although 47/193 (24.3{\%}) of normal controls were heterozygous for the 187G mutation only two of these carried the 845A mutation. If the 187G mutation complemented the 845A mutation with high penetrance in causing hemochromatosis, then the population frequency of the two genes would require that a high proportion of patients with hemochromatosis be heterozygous for 845A and 187G. Instead, the frequency of homozygotes for the 845A mutation was much higher than that of the 845A/187G genotype. Based on our data, the penetrance of the 845A/187G genotype is only 1.5{\%} and based on the data of Feder et al. only 0.5{\%}. In contrast, the penetrance of the homozygous 845A/845A genotype seems to be very high. Thus, screening for this genotype should be very useful.",
author = "Ernest Beutler and Terri Gelbart and Carol West and Pauline Lee and Michele Adams and Ryan Blackstone and Paul Pockros and Michael Kosty and Venditti, {Charles P.} and Phatak, {Pradyumna D.} and Seese, {Nicole K.} and Chorney, {Karen A.} and {Ten Elshof}, {Amy E.} and Gerhard, {Glenn S.} and Chorney, {Michael J.}",
year = "1996",
month = "1",
day = "1",
doi = "10.1006/bcmd.1996.0027",
language = "English (US)",
volume = "22",
pages = "187--194",
journal = "Blood Cells, Molecules, and Diseases",
issn = "1079-9796",
publisher = "Academic Press Inc.",
number = "2",

}

Beutler, E, Gelbart, T, West, C, Lee, P, Adams, M, Blackstone, R, Pockros, P, Kosty, M, Venditti, CP, Phatak, PD, Seese, NK, Chorney, KA, Ten Elshof, AE, Gerhard, GS & Chorney, MJ 1996, 'Mutation analysis in hereditary hemochromatosis', Blood Cells, Molecules, and Diseases, vol. 22, no. 2, pp. 187-194. https://doi.org/10.1006/bcmd.1996.0027

Mutation analysis in hereditary hemochromatosis. / Beutler, Ernest; Gelbart, Terri; West, Carol; Lee, Pauline; Adams, Michele; Blackstone, Ryan; Pockros, Paul; Kosty, Michael; Venditti, Charles P.; Phatak, Pradyumna D.; Seese, Nicole K.; Chorney, Karen A.; Ten Elshof, Amy E.; Gerhard, Glenn S.; Chorney, Michael J.

In: Blood Cells, Molecules, and Diseases, Vol. 22, No. 2, 01.01.1996, p. 187-194.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutation analysis in hereditary hemochromatosis

AU - Beutler, Ernest

AU - Gelbart, Terri

AU - West, Carol

AU - Lee, Pauline

AU - Adams, Michele

AU - Blackstone, Ryan

AU - Pockros, Paul

AU - Kosty, Michael

AU - Venditti, Charles P.

AU - Phatak, Pradyumna D.

AU - Seese, Nicole K.

AU - Chorney, Karen A.

AU - Ten Elshof, Amy E.

AU - Gerhard, Glenn S.

AU - Chorney, Michael J.

PY - 1996/1/1

Y1 - 1996/1/1

N2 - The DNA of 147 patients of European origin clinically diagnosed with idiopathic hemochromatosis and 193 controls was examined for mutations of the HLA-H gene at nt 845 and nt 187. One hundred twenty-one (82.3%) of the hemochromatosis patients were homozygous and 10 (6.8%) heterozygous for the 845A (C282Y) mutation. All of the homozygous patients were also homozygous for nt 187C, and all 845A heterozygotes had at least one copy of 187C. Thus, the nt 845 and nt 187 mutations were in complete linkage disequilibrium; nt 187 was a C on all chromosomes with the 845A mutation. Eight of the 10 heterozygotes for 845A were heterozygous for 187G(H63D). The excess of heterozygotes at both nt 187 and nt 845 suggested either the presence of as yet undiscovered mutations existing in trans with 845A and in linkage disequilibrium with 187G, or that the 187G itself is a deleterious mutation, which in concert with the 845A can give rise to hemochromatosis. None of the 193 normal controls were homozygous for 845A and 29/193 (15%) were heterozygous for 845A. Although 47/193 (24.3%) of normal controls were heterozygous for the 187G mutation only two of these carried the 845A mutation. If the 187G mutation complemented the 845A mutation with high penetrance in causing hemochromatosis, then the population frequency of the two genes would require that a high proportion of patients with hemochromatosis be heterozygous for 845A and 187G. Instead, the frequency of homozygotes for the 845A mutation was much higher than that of the 845A/187G genotype. Based on our data, the penetrance of the 845A/187G genotype is only 1.5% and based on the data of Feder et al. only 0.5%. In contrast, the penetrance of the homozygous 845A/845A genotype seems to be very high. Thus, screening for this genotype should be very useful.

AB - The DNA of 147 patients of European origin clinically diagnosed with idiopathic hemochromatosis and 193 controls was examined for mutations of the HLA-H gene at nt 845 and nt 187. One hundred twenty-one (82.3%) of the hemochromatosis patients were homozygous and 10 (6.8%) heterozygous for the 845A (C282Y) mutation. All of the homozygous patients were also homozygous for nt 187C, and all 845A heterozygotes had at least one copy of 187C. Thus, the nt 845 and nt 187 mutations were in complete linkage disequilibrium; nt 187 was a C on all chromosomes with the 845A mutation. Eight of the 10 heterozygotes for 845A were heterozygous for 187G(H63D). The excess of heterozygotes at both nt 187 and nt 845 suggested either the presence of as yet undiscovered mutations existing in trans with 845A and in linkage disequilibrium with 187G, or that the 187G itself is a deleterious mutation, which in concert with the 845A can give rise to hemochromatosis. None of the 193 normal controls were homozygous for 845A and 29/193 (15%) were heterozygous for 845A. Although 47/193 (24.3%) of normal controls were heterozygous for the 187G mutation only two of these carried the 845A mutation. If the 187G mutation complemented the 845A mutation with high penetrance in causing hemochromatosis, then the population frequency of the two genes would require that a high proportion of patients with hemochromatosis be heterozygous for 845A and 187G. Instead, the frequency of homozygotes for the 845A mutation was much higher than that of the 845A/187G genotype. Based on our data, the penetrance of the 845A/187G genotype is only 1.5% and based on the data of Feder et al. only 0.5%. In contrast, the penetrance of the homozygous 845A/845A genotype seems to be very high. Thus, screening for this genotype should be very useful.

UR - http://www.scopus.com/inward/record.url?scp=0030221927&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030221927&partnerID=8YFLogxK

U2 - 10.1006/bcmd.1996.0027

DO - 10.1006/bcmd.1996.0027

M3 - Article

C2 - 8931958

AN - SCOPUS:0030221927

VL - 22

SP - 187

EP - 194

JO - Blood Cells, Molecules, and Diseases

JF - Blood Cells, Molecules, and Diseases

SN - 1079-9796

IS - 2

ER -

Beutler E, Gelbart T, West C, Lee P, Adams M, Blackstone R et al. Mutation analysis in hereditary hemochromatosis. Blood Cells, Molecules, and Diseases. 1996 Jan 1;22(2):187-194. https://doi.org/10.1006/bcmd.1996.0027