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Loss-of-function variants in the <jats:italic>LPL<\/jats:italic> gene are associated with hypertriglyceridemia (HTG) and HTG-related diseases. Unlike nonsense, frameshift and canonical GT-AG splice site variants, a pathogenic role for clinically identified <jats:italic>LPL<\/jats:italic> missense variants should generally be confirmed by functional analysis. Herein, we describe the clinical and functional analysis of a rare <jats:italic>LPL<\/jats:italic> missense variant.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Chinese patients with HTG-associated acute pancreatitis (HTG-AP) were screened for rare nonsense, frameshift, missense or canonical GT-AG splice site variants in <jats:italic>LPL<\/jats:italic> and four other lipid metabolism-related genes (<jats:italic>APOC2<\/jats:italic>, <jats:italic>APOA5<\/jats:italic>, <jats:italic>GPIHBP1<\/jats:italic> and <jats:italic>LMF1<\/jats:italic>) by Sanger sequencing. The functional consequences of the <jats:italic>LPL<\/jats:italic> missense variant of interest were characterized by in vitro expression in HEK-293T and COS-7 cells followed by Western blot and LPL activity assays.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Five unrelated HTG-AP patients were found to be heterozygous for a rare East Asian-specific <jats:italic>LPL<\/jats:italic> missense variant, c.862G\u2009&gt;\u2009A (p.Ala288Thr). All five patients were adult males, and all were overweight and had a long history of alcohol consumption. Transfection of <jats:italic>LPL<\/jats:italic> wild-type and c.862G\u2009&gt;\u2009A expression vectors into two cell lines followed by Western blot analysis served to exclude the possibility that the p.Ala288Thr missense variant either impaired protein synthesis or increased protein degradation. Contrary to a previous functional study that claimed that p.Ala288Thr had a severe impact on LPL function (reportedly having 36% normal activity), our experiments consistently demonstrated that the variant had a comparatively mild effect on LPL functional activity, which was mediated through its impact upon LPL protein secretion (~\u200920% reduced secretion compared to wild-type).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>In this study, we identified the East Asian-specific <jats:italic>LPL<\/jats:italic> c.862G\u2009&gt;\u2009A (p.Ala288Thr) missense variant in five unrelated HTG-AP patients. We demonstrated that this variant exerted only a relatively mild effect on LPL function in two cell lines. Heterozygosity for this <jats:italic>LPL<\/jats:italic> variant may have combined with alcohol consumption to trigger HTG-AP in these patients.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12944-023-01875-3","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T11:02:57Z","timestamp":1691406177000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The East Asian-specific LPL p.Ala288Thr (c.862G\u2009&gt;\u2009A) missense variant exerts a mild effect on protein function"],"prefix":"10.1186","volume":"22","author":[{"given":"Yuepeng","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guofu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Pu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiwei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baiqiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N.","family":"Cooper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Min","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,8,7]]},"reference":[{"key":"1875_CR1","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1093\/eurheartj\/ehz785","volume":"41","author":"U Laufs","year":"2020","unstructured":"Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. 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