{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:54:56Z","timestamp":1781110496491,"version":"3.54.1"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"9","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,4,24]]},"abstract":"<jats:p>\n                    Hereditary hemochromatosis (HH) is a common chronic human genetic disorder whose hallmark is systemic iron overload. Homozygosity for a mutation in the MHC class I heavy chain paralogue gene\n                    <jats:italic>HFE<\/jats:italic>\n                    has been found to be a primary cause of HH. However, many individuals homozygous for the defective allele of\n                    <jats:italic>HFE<\/jats:italic>\n                    do not develop iron overload, raising the possibility that genetic variation in modifier loci contributes to the HH phenotype. Mice deficient in the product of the \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -microglobulin (\u03b2\n                    <jats:sub>2<\/jats:sub>\n                    M) class I light chain fail to express HFE and other MHC class I family proteins, and they have been found to manifest many characteristics of the HH phenotype. To determine whether natural genetic variation plays a role in controlling iron overload, we performed classical genetic analysis of the iron-loading phenotype in \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    M-deficient mice in the context of different genetic backgrounds. Strain background was found to be a major determinant in iron loading. Sex played a role that was less than that of strain background but still significant. Resistance and susceptibility to iron overload segregated as complex genetic traits in F\n                    <jats:sub>1<\/jats:sub>\n                    and back-cross progeny. These results suggest the existence of naturally variant autosomal and Y chromosome-linked modifier loci that, in the context of mice genetically predisposed by virtue of a \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    M deficiency, can profoundly influence the severity of iron loading. These results thus provide a genetic explanation for some of the variability of the HH phenotype.\n                  <\/jats:p>","DOI":"10.1073\/pnas.091088998","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:37:36Z","timestamp":1027679856000},"page":"5170-5174","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":40,"title":["Naturally variant autosomal and sex-linked loci determine the severity of iron overload in \u03b2\n                    <sub>2<\/sub>\n                    -microglobulin-deficient mice"],"prefix":"10.1073","volume":"98","author":[{"given":"Thomas J.","family":"Sproule","sequence":"first","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609; Queensland Institute of Medical Research, Brisbane 4029 QLD, Australia; and Division of Gastroenterology and Hepatology, Department of Internal Medicine, Department of Pediatrics, and the Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Jazwinska","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609; Queensland Institute of Medical Research, Brisbane 4029 QLD, Australia; and Division of Gastroenterology and Hepatology, Department of Internal Medicine, Department of Pediatrics, and the Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Britton","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609; Queensland Institute of Medical Research, Brisbane 4029 QLD, Australia; and Division of Gastroenterology and Hepatology, Department of Internal Medicine, Department of Pediatrics, and the Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce R.","family":"Bacon","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609; Queensland Institute of Medical Research, Brisbane 4029 QLD, Australia; and Division of Gastroenterology and Hepatology, Department of Internal Medicine, Department of Pediatrics, and the Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Fleming","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609; Queensland Institute of Medical Research, Brisbane 4029 QLD, Australia; and Division of Gastroenterology and Hepatology, Department of Internal Medicine, Department of Pediatrics, and the Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William S.","family":"Sly","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609; Queensland Institute of Medical Research, Brisbane 4029 QLD, Australia; and Division of Gastroenterology and Hepatology, Department of Internal Medicine, Department of Pediatrics, and the Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derry C.","family":"Roopenian","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609; Queensland Institute of Medical Research, Brisbane 4029 QLD, Australia; and Division of Gastroenterology and Hepatology, Department of Internal Medicine, Department of Pediatrics, and the Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,4,17]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"1435","volume-title":"Mendelian Inheritance in Man","author":"McKusick V A","year":"1992","unstructured":"V A McKusick Mendelian Inheritance in Man (Johns Hopkins Univ. 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