{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:43:31Z","timestamp":1762868611661,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T00:00:00Z","timestamp":1631577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>Familial hypercholesterolemia (FH) is the most common genetic disorder of lipid metabolism, characterized by increased levels of total and LDL plasma cholesterol, which leads to premature atherosclerosis and coronary heart disease. FH phenotype has considerable genetic heterogeneity and phenotypic variability, depending on LDL receptor activity and lifestyle. To improve diagnosis and patient management, here, we characterized two single nucleotide missense substitutions at Methionine 1 of the human LDLR gene (c.1A&gt;T\/p.(Met1Leu) and c.1A&gt;C\/p.(Met1Leu)). We used a combination of Western blot, flow cytometry, and luciferase assays to determine the effects of both variants on the expression, activity, and synthesis of LDLR. Our data show that both variants can mediate translation initiation, although the expression of variant c.1A&gt;T is very low. Both variants are in the translation initiation codon and codify for the same amino acid p.(Met1Leu), yet they lead to different levels of impairment on LDLR expression and activity, corroborating different efficiencies of the translation initiation at these non-canonical initiation codons. The functional data of these variants allowed for an improved American College of Medical Genetics (ACMG) classification for both variants, which can allow a more personalized choice of the lipid-lowering treatment and dyslipidemia management, ultimately improving patients\u2019 prognosis.<\/jats:p>","DOI":"10.3390\/biomedicines9091219","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T21:47:21Z","timestamp":1631656041000},"page":"1219","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3725-0268","authenticated-orcid":false,"given":"Rafael","family":"Gra\u00e7a","sequence":"first","affiliation":[{"name":"Departamento de Promo\u00e7\u00e3o da Sa\u00fade e Preven\u00e7\u00e3o de Doen\u00e7as N\u00e3o Transmiss\u00edveis, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, 1600-609 Lisbon, Portugal"},{"name":"BioISI\u2014Biosystems & Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisbon, Portugal"}]},{"given":"Rafael","family":"Fernandes","sequence":"additional","affiliation":[{"name":"BioISI\u2014Biosystems & Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisbon, Portugal"},{"name":"Departamento de Gen\u00e9tica Humana, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, 1600-609 Lisbon, Portugal"}]},{"given":"Ana Catarina","family":"Alves","sequence":"additional","affiliation":[{"name":"Departamento de Promo\u00e7\u00e3o da Sa\u00fade e Preven\u00e7\u00e3o de Doen\u00e7as N\u00e3o Transmiss\u00edveis, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, 1600-609 Lisbon, Portugal"},{"name":"BioISI\u2014Biosystems & Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisbon, Portugal"}]},{"given":"Juliane","family":"Menezes","sequence":"additional","affiliation":[{"name":"BioISI\u2014Biosystems & Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisbon, Portugal"},{"name":"Departamento de Gen\u00e9tica Humana, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, 1600-609 Lisbon, Portugal"}]},{"given":"Lu\u00edsa","family":"Rom\u00e3o","sequence":"additional","affiliation":[{"name":"BioISI\u2014Biosystems & Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisbon, Portugal"},{"name":"Departamento de Gen\u00e9tica Humana, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, 1600-609 Lisbon, Portugal"}]},{"given":"Mafalda","family":"Bourbon","sequence":"additional","affiliation":[{"name":"Departamento de Promo\u00e7\u00e3o da Sa\u00fade e Preven\u00e7\u00e3o de Doen\u00e7as N\u00e3o Transmiss\u00edveis, Instituto Nacional de Sa\u00fade Doutor Ricardo Jorge, 1600-609 Lisbon, Portugal"},{"name":"BioISI\u2014Biosystems & Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1126\/science.3513311","article-title":"A receptor-mediated pathway for cholesterol homeostasis","volume":"232","author":"Brown","year":"1986","journal-title":"Science (80-)"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/bmjopen-2017-016461","article-title":"Estimating the prevalence of heterozygous familial hypercholesterolaemia: A systematic review and meta-analysis","volume":"7","author":"Akioyamen","year":"2017","journal-title":"BMJ Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41569-018-0052-6","article-title":"The complex molecular genetics of familial hypercholesterolaemia","volume":"16","author":"Berberich","year":"2019","journal-title":"Nat. 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