{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T13:45:18Z","timestamp":1780321518170,"version":"3.54.1"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Chinese National Natural Science Foundation","doi-asserted-by":"crossref","award":["82170521"],"award-info":[{"award-number":["82170521"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Shanghai Natural Science Foundation of China","award":["21ZR1449500"],"award-info":[{"award-number":["21ZR1449500"]}]},{"name":"Foundation of Shanghai Municipal Health Commission","award":["202140263"],"award-info":[{"award-number":["202140263"]}]},{"name":"Fundamental Research Funds for Central Universities","award":["NO.22120190211"],"award-info":[{"award-number":["NO.22120190211"]}]},{"name":"Foundation of Chongming","award":["CKY2021-21, CKY2020-29"],"award-info":[{"award-number":["CKY2021-21, CKY2020-29"]}]},{"name":"Clinical Research Plan of SHDC","award":["SHDC2020CR4065"],"award-info":[{"award-number":["SHDC2020CR4065"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Lipids Health Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder. The primary objective of this study was to identify the major pathogenic mutations in a Chinese family with FH.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Whole-genome sequencing (WGS) was used to identify variants of FH-related genes, including low-density lipoprotein receptor <jats:italic>(LDLR)<\/jats:italic>, apolipoprotein B <jats:italic>(APOB)<\/jats:italic>, and proprotein convertase subtilisin\/kexin 9 <jats:italic>(PCSK9)<\/jats:italic>. Bioinformatics software was used to predict signal peptides, transmembrane structures, and spatial construction information of the mutated sequences. Western blotting was performed on the mutant protein to determine the presence of the major structural domains of the LDLR. The <jats:italic>PCSK9<\/jats:italic> and <jats:italic>APOB<\/jats:italic> genes were screened and analyzed. Moreover, the proband and his brother were treated with a PCSK9 inhibitor for 1 year, and the effect of the treatment on lipid levels was assessed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>WGS revealed two potentially pathogenic mutations in the <jats:italic>LDLR<\/jats:italic> gene. One was a novel mutation, c.497delinsGGATCCCCCAGCTGCATCCCCCAG (p. Ala166fs), and the other was a known pathogenic mutation, c.2054C&gt;T (p. Pro685Leu). Bioinformatics prediction and in vitro experiments revealed that the novel mutation could not be expressed on the cell membrane. Numerous gene variants were identified in the <jats:italic>APOB<\/jats:italic> gene that may have a significant impact on the family members with FH. Thus, it is suggested that the severe manifestation of FH in the proband primarily resulted from the cumulative genetic effects of variants in both <jats:italic>LDLR<\/jats:italic> and <jats:italic>APOB<\/jats:italic>. However, a subsequent study indicated that treatment with a PCSK9 inhibitor (Evolocumab) did not significantly reduce the blood lipid levels in the proband or his brother.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The cumulative effect of <jats:italic>LDLR<\/jats:italic> and <jats:italic>APOB<\/jats:italic> variants was the primary cause of elevated blood lipid levels in this family. However, PCSK9 inhibitor therapy did not appear to be beneficial for the proband. This study emphasizes the importance of genetic testing in determining the most suitable treatment options for patients with FH.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12944-023-01935-8","type":"journal-article","created":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T17:01:56Z","timestamp":1697648516000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Screening and verifying the mutations in the LDLR and APOB genes in a Chinese family with familial hypercholesterolemia"],"prefix":"10.1186","volume":"22","author":[{"given":"Xian","family":"Lv","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqing","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuad A.","family":"Abdu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingfeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenliang","family":"Che","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,18]]},"reference":[{"issue":"6","key":"1935_CR1","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1038\/s41569-019-0325-8","volume":"17","author":"GF Watts","year":"2020","unstructured":"Watts GF, Gidding SS, Mata P, Pang J, Sullivan DR, Yamashita S, et al. Familial hypercholesterolaemia: evolving knowledge for designing adaptive models of care. Nat Rev Cardiol. 2020;17(6):360\u201377.","journal-title":"Nat Rev Cardiol"},{"issue":"6","key":"1935_CR2","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1016\/j.jacc.2018.05.044","volume":"72","author":"AC Sturm","year":"2018","unstructured":"Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM, et al. Clinical genetic testing for familial hypercholesterolemia. J Am Coll Cardiol. 2018;72(6):662\u201380.","journal-title":"J Am Coll Cardiol"},{"key":"1935_CR3","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1016\/j.atherosclerosis.2018.08.022","volume":"277","author":"YC Hsiung","year":"2018","unstructured":"Hsiung YC, Lin PC, Chen CS, Tung YC, Yang WS, Chen PL, et al. Identification of a novel LDLR disease-causing variant using capture-based next-generation sequencing screening of familial hypercholesterolemia patients in Taiwan. Atherosclerosis. 2018;277:440\u20137.","journal-title":"Atherosclerosis"},{"key":"1935_CR4","doi-asserted-by":"crossref","unstructured":"Rodriguez-Jimenez C, de la Pena G, Sanguino J, Poyatos-Pelaez S, Carazo A, Martinez-Hernandez PL et al. Identification and functional analysis of APOB Variants in a cohort of hypercholesterolemic patients. Int J Mol Sci 2023; 24(8).","DOI":"10.3390\/ijms24087635"},{"key":"1935_CR5","doi-asserted-by":"crossref","unstructured":"He Y, Rodrigues RM, Wang XL, Seo W, Ma J, Hwang S et al. Neutrophil-to-hepatocyte communication via LDLR-dependent mir-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis. J Clin Invest. 2021; 131(3).","DOI":"10.1172\/JCI141513"},{"key":"1935_CR6","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1146\/annurev.biochem.74.082803.133354","volume":"74","author":"H Jeon","year":"2005","unstructured":"Jeon H, Blacklow SC. Structure and physiologic function of the low-density lipoprotein receptor. Annu Rev Biochem. 2005;74:535\u201362.","journal-title":"Annu Rev Biochem"},{"key":"1935_CR7","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.atherosclerosis.2018.06.819","volume":"277","author":"AC Alves","year":"2018","unstructured":"Alves AC, Benito-Vicente A, Medeiros AM, Reeves K, Martin C, Bourbon M. Further evidence of novel APOB mutations as a cause of familial hypercholesterolaemia. Atherosclerosis. 2018;277:448\u201356.","journal-title":"Atherosclerosis"},{"issue":"2","key":"1935_CR8","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1111\/joim.13577","volume":"293","author":"M Abifadel","year":"2023","unstructured":"Abifadel M, Boileau C. Genetic and molecular architecture of familial hypercholesterolemia. J Intern Med. 2023;293(2):144\u201365.","journal-title":"J Intern Med"},{"issue":"2","key":"1935_CR9","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1007\/s11883-014-0482-5","volume":"17","author":"S Singh","year":"2015","unstructured":"Singh S, Bittner V. Familial hypercholesterolemia\u2013epidemiology, diagnosis, and screening. Curr Atheroscler Rep. 2015;17(2):482.","journal-title":"Curr Atheroscler Rep"},{"issue":"32","key":"1935_CR10","doi-asserted-by":"publisher","first-page":"2146","DOI":"10.1093\/eurheartj\/ehu274","volume":"35","author":"M Cuchel","year":"2014","unstructured":"Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the european atherosclerosis society. Eur Heart J. 2014;35(32):2146\u2013U2100.","journal-title":"Eur Heart J"},{"issue":"1\u20132","key":"1935_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jjcc.2017.07.002","volume":"71","author":"M Ogura","year":"2018","unstructured":"Ogura M. PCSK9 inhibition in the management of familial hypercholesterolemia. J Cardiol. 2018;71(1\u20132):1\u20137.","journal-title":"J Cardiol"},{"key":"1935_CR12","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.atherosclerosis.2022.03.012","volume":"347","author":"D Noto","year":"2022","unstructured":"Noto D, Spina R, Giammanco A, Barbagallo CM, Ganci A, Scrimali C, et al. Diagnosis of familial hypercholesterolemia in a large cohort of italian genotyped hypercholesterolemic patients. Atherosclerosis. 2022;347:63\u20137.","journal-title":"Atherosclerosis"},{"issue":"10","key":"1935_CR13","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1038\/nmeth.1701","volume":"8","author":"TN Petersen","year":"2011","unstructured":"Petersen TN, Brunak S, von Heijne G, Nielsen H. SignalP 4.0: discriminating signal peptides from transmembrane regions. Nat Methods. 2011;8(10):785\u20136.","journal-title":"Nat Methods"},{"issue":"3","key":"1935_CR14","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1006\/jmbi.2000.4315","volume":"305","author":"A Krogh","year":"2001","unstructured":"Krogh A, Larsson B, von Heijne G, Sonnhammer ELL. Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J Mol Biol. 2001;305(3):567\u201380.","journal-title":"J Mol Biol"},{"issue":"W1","key":"1935_CR15","doi-asserted-by":"publisher","first-page":"W296","DOI":"10.1093\/nar\/gky427","volume":"46","author":"A Waterhouse","year":"2018","unstructured":"Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46(W1):W296\u2013W303.","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"1935_CR16","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1136\/jmedgenet-2016-104054","volume":"54","author":"S Leigh","year":"2017","unstructured":"Leigh S, Futema M, Whittall R, Taylor-Beadling A, Williams M, den Dunnen JT, et al. The UCL low-density lipoprotein receptor gene variant database: pathogenicity update. J Med Genet. 2017;54(4):217\u201323.","journal-title":"J Med Genet"},{"key":"1935_CR17","doi-asserted-by":"crossref","unstructured":"Jiang L, Sun LY, Dai YF, Yang SW, Zhang F, Wang LY. The distribution and characteristics of LDL receptor mutations in China: a systematic review. Sci Rep 2015; 5.","DOI":"10.1038\/srep17272"},{"issue":"6","key":"1935_CR18","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/j.ejcb.2018.06.003","volume":"97","author":"H Owji","year":"2018","unstructured":"Owji H, Nezafat N, Negandaripour M, Hajiebrahimi A, Ghasemi Y. A comprehensive review of signal peptides: structure, roles, and applications. Eur J Cell Biol. 2018;97(6):422\u201341.","journal-title":"Eur J Cell Biol"},{"issue":"W1","key":"1935_CR19","doi-asserted-by":"publisher","first-page":"W252","DOI":"10.1093\/nar\/gku340","volume":"42","author":"M Biasini","year":"2014","unstructured":"Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, et al. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res. 2014;42(W1):W252\u20138.","journal-title":"Nucleic Acids Res"},{"key":"1935_CR20","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1146\/annurev-pathol-012513-104649","volume":"10","author":"SA Oakes","year":"2015","unstructured":"Oakes SA, Papa FR. The role of endoplasmic reticulum stress in Human Pathology. Annu Rev Pathol-Mech. 2015;10:173\u201394.","journal-title":"Annu Rev Pathol-Mech"},{"issue":"1","key":"1935_CR21","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1007\/s00018-015-2052-6","volume":"73","author":"DS Schwarz","year":"2016","unstructured":"Schwarz DS, Blower MD. The endoplasmic reticulum: structure, function and response to cellular signaling. Cell Mol Life Sci. 2016;73(1):79\u201394.","journal-title":"Cell Mol Life Sci"},{"key":"1935_CR22","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1146\/annurev-genet-111212-133522","volume":"47","author":"T Pan","year":"2013","unstructured":"Pan T. Adaptive translation as a mechanism of stress response and adaptation. Annu Rev Genet. 2013;47:121\u201337.","journal-title":"Annu Rev Genet"},{"issue":"7\u20138","key":"1935_CR23","first-page":"769","volume":"25","author":"RE Yao","year":"2012","unstructured":"Yao RE, Wang J, Geng J, Zheng ZJ, Yu TT, Yu YG, et al. Identification of LDLR mutations in two chinese pedigrees with familial hypercholesterolemia. J Pediatr Endocrinol Metabolism. 2012;25(7\u20138):769\u201373.","journal-title":"J Pediatr Endocrinol Metabolism"},{"key":"1935_CR24","doi-asserted-by":"crossref","unstructured":"Sarkar A, Panati K, Narala VR. Code inside the codon: the role of synonymous mutations in regulating splicing machinery and its impact on disease. Mutat Res-Rev Mutat. 2022; 790.","DOI":"10.1016\/j.mrrev.2022.108444"},{"issue":"7","key":"1935_CR25","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.tig.2014.04.006","volume":"30","author":"RC Hunt","year":"2014","unstructured":"Hunt RC, Simhadri VL, Iandoli M, Sauna ZE, Kimchi-Sarfaty C. Exposing synonymous mutations. Trends Genet. 2014;30(7):308\u201321.","journal-title":"Trends Genet"},{"issue":"3","key":"1935_CR26","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1080\/14656566.2019.1702970","volume":"21","author":"A Pasta","year":"2020","unstructured":"Pasta A, Cremonini AL, Pisciotta L, Buscaglia A, Porto I, Barra F, et al. PCSK9 inhibitors for treating hypercholesterolemia. Expert Opin Pharmaco. 2020;21(3):353\u201363.","journal-title":"Expert Opin Pharmaco"}],"container-title":["Lipids in Health and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12944-023-01935-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12944-023-01935-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12944-023-01935-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,18]],"date-time":"2023-11-18T06:02:35Z","timestamp":1700287355000},"score":1,"resource":{"primary":{"URL":"https:\/\/lipidworld.biomedcentral.com\/articles\/10.1186\/s12944-023-01935-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,18]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["1935"],"URL":"https:\/\/doi.org\/10.1186\/s12944-023-01935-8","relation":{},"ISSN":["1476-511X"],"issn-type":[{"value":"1476-511X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,18]]},"assertion":[{"value":"29 June 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 October 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 October 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Ethics Committee of Shanghai Tenth People\u2019s Hospital (22K127) and all study participants provided written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent for publication was obtained from all participants.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"175"}}