{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T20:10:51Z","timestamp":1767557451435},"reference-count":33,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2012,5,25]],"date-time":"2012-05-25T00:00:00Z","timestamp":1337904000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2012,8]]},"abstract":"Summary<\/jats:title>Hereditary haemochromatosis (HH<\/jats:styled-content>) is an autosomal recessive disorder characterized by excessive intestinal iron absorption resulting in increased pathological body iron stores. It is typically associated with homozygosity for the c.845G<\/jats:styled-content>>A<\/jats:styled-content> (p.C<\/jats:styled-content>282Y<\/jats:styled-content>) mutation in the \nHFE<\/jats:italic>\n<\/jats:styled-content> gene. However, other \nHFE<\/jats:italic>\n<\/jats:styled-content> alterations have been reported in affected individuals but their association with the disease is unclear. This study analysed the functional consequences of two \nHFE<\/jats:italic>\n<\/jats:styled-content> mutations, c.829G<\/jats:styled-content>>A<\/jats:styled-content> (p.E<\/jats:styled-content>277K<\/jats:styled-content>) and c.884T<\/jats:styled-content>>C<\/jats:styled-content> (p.V<\/jats:styled-content>295A<\/jats:styled-content>). Firstly, it was shown that c.829G<\/jats:styled-content>>A<\/jats:styled-content> affects the \nHFE<\/jats:italic>\n<\/jats:styled-content> splicing by diminishing the full length HFE<\/jats:styled-content> and ivs4_66bp inclusion transcript levels, while increasing the amount of exon 4 skipping transcript. Immunofluorescent techniques showed that the HFE<\/jats:styled-content>_E<\/jats:styled-content>277K<\/jats:styled-content> protein had a diffuse distribution (similar to HFE<\/jats:styled-content>_C<\/jats:styled-content>282Y<\/jats:styled-content>) while HFE<\/jats:styled-content>_V<\/jats:styled-content>295A<\/jats:styled-content> presented at the cell surface and perinuclear compartments (resembling HFE<\/jats:styled-content>_wt). Immunoprecipitation assays revealed a decreased association of HFE<\/jats:styled-content>_E<\/jats:styled-content>277K<\/jats:styled-content> and HFE<\/jats:styled-content>_V<\/jats:styled-content>295A<\/jats:styled-content> with both \u03b22\u2010microglobulin (B<\/jats:styled-content>2M<\/jats:styled-content>; 38\u00a0\u00b1\u00a07% and 66\u00a0\u00b1\u00a08%, respectively) and transferrin receptor (TFRC<\/jats:styled-content>, also termed TFR<\/jats:styled-content>1) (58\u00a0\u00b1\u00a02% and 49\u00a0\u00b1\u00a016%, respectively). Herein, we prove that both mutations partially abrogate HFE<\/jats:styled-content> association with B<\/jats:styled-content>2M<\/jats:styled-content> and TFRC<\/jats:styled-content>, crucial for its correct processing and cell surface presentation. Although E<\/jats:styled-content>277K<\/jats:styled-content> has a more deleterious effect than V<\/jats:styled-content>295A<\/jats:styled-content>, we propose that both mutations may play a role in the development of hereditary haemochromatosis.<\/jats:p>","DOI":"10.1111\/j.1365-2141.2012.09164.x","type":"journal-article","created":{"date-parts":[[2012,5,25]],"date-time":"2012-05-25T07:35:38Z","timestamp":1337931338000},"page":"399-408","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The functional significance of E<\/scp>277K<\/scp> and V<\/scp>295A HFE<\/i><\/scp> mutations"],"prefix":"10.1111","volume":"158","author":[{"given":"Bruno","family":"Silva","sequence":"first","affiliation":[{"name":"Departamento de Gen\u00e9tica Instituto Nacional de Sa\u00fade Dr. Ricardo Jorge Lisboa Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rute","family":"Martins","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica Instituto Nacional de Sa\u00fade Dr. Ricardo Jorge Lisboa Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Proen\u00e7a","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica Instituto Nacional de Sa\u00fade Dr. Ricardo Jorge Lisboa Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Fleming","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Imuno\u2010hemoterapia Hospital de Santa Maria Lisboa Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula","family":"Faustino","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica Instituto Nacional de Sa\u00fade Dr. Ricardo Jorge Lisboa Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,5,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2010.029751"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M702672200"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.21524"},{"key":"e_1_2_8_5_1","first-page":"405","article-title":"Gene symbol: HFE","volume":"114","author":"Bento M.C.","year":"2004","journal-title":"Disease: Haemochromatosis. 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