Identification and Functional Characterization of a Low-Density Lipoprotein Receptor Gene Pathogenic Variant in Familial Hypercholesterolemia

被引:4
作者
Shu, Hong-Yan [1 ]
Zhang, Wei [1 ]
Zheng, Cong-Cong [1 ]
Gao, Man-Yun [1 ]
Li, Yong-Cun [1 ]
Wang, Yan-Gang [2 ]
机构
[1] Zibo Municipal Hosp, Dept Endocrinol & Metab Dis, Zibo, Peoples R China
[2] Qingdao Univ, Dept Endocrinol & Metab Dis, Affiliated Hosp, Qingdao, Peoples R China
基金
中国国家自然科学基金;
关键词
low-density lipoprotein receptor gene; genomic variant; familial hypercholesterolemia; functional analyses; Golgi apparatus; PREVALENCE; MANAGEMENT; DISEASE; LDLR;
D O I
10.3389/fgene.2021.650077
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
We report a single-point variant of low-density lipoprotein receptor (LDLR) in a Chinese proband with a clinical diagnosis of familial hypercholesterolemia (FH) with a comprehensive functional analysis. Target exome capture-based next-generation sequencing was used for sequencing and identification of genomic variants in the LDLR gene. The expression, cellular location, and function of the mutant LDLR were analyzed. Sequencing of LDLR in FH patients indicated a point variant of single-base substitution (G < A) at a position of 2389 in the 16th exon, which led to a loss of the 16th exon in the LDLR messenger RNA. This genomic variant was found to cause exon 16 deletion in the mutant LDLR protein. Subsequent functional analyses showed that the mutant LDLR was retained in the Golgi apparatus and rarely expressed in the cellular membranes of HepG2 cells. Accordingly, the intake ability of HepG2 cells with the mutant LDLR was significantly reduced (P < 0.05). In conclusion, our results suggest that a mutant with a single-base substitution (c. 2389G > A) in the 16th exon of the LDLR gene was associated with miscleavage of messenger RNA and the retention of mutant LDLR in the Golgi apparatus, which revealed a pathogenic variant in LDLR underlying the pathogenesis of FH.
引用
收藏
页数:8
相关论文
共 29 条
  • [1] Familial Hypercholesterolemia in the Danish General Population: Prevalence, Coronary Artery Disease, and Cholesterol-Lowering Medication
    Benn, Marianne
    Watts, Gerald F.
    Tybjaerg-Hansen, Anne
    Nordestgaard, Borge G.
    [J]. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2012, 97 (11) : 3956 - 3964
  • [2] 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR)
    Catapano, Alberico L.
    Graham, Ian
    De Backer, Guy
    Wiklund, Olov
    Chapman, M. John
    Drexel, Heinz
    Hoes, Arno W.
    Jennings, Catriona S.
    Landmesser, Ulf
    Pedersen, Terje R.
    Reiner, Zeljko
    Riccardi, Gabriele
    Taskinen, Marja-Riita
    Tokgozoglu, Lale
    Verschuren, W. M. Monique
    Vlachopoulos, Charalambos
    Wood, David A.
    Luis Zamorano, Jose
    [J]. ATHEROSCLEROSIS, 2016, 253 : 281 - 344
  • [3] Lipoprotein metabolism in familial hypercholesterolemia
    Chemello, Kevin
    Garcia-Nafria, Javier
    Gallo, Antonio
    Martin, Cesar
    Lambert, Gilles
    Blom, Dirk
    [J]. JOURNAL OF LIPID RESEARCH, 2021, 62
  • [4] Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES)
    de Ferranti, Sarah D.
    Rodday, Angie Mae
    Mendelson, Michael M.
    Wong, John B.
    Leslie, Laurel K.
    Sheldrick, R. Christopher
    [J]. CIRCULATION, 2016, 133 (11) : 1067 - 1072
  • [5] Defesche Joep C, 2004, Semin Vasc Med, V4, P5
  • [6] Practical definitions of severe versus familial hypercholesterolaemia and hypertriglyceridaemia for adult clinical practice
    Garg, Ankit
    Garg, Vinay
    Hegele, Robert A.
    Lewis, Gary F.
    [J]. LANCET DIABETES & ENDOCRINOLOGY, 2019, 7 (11) : 880 - 886
  • [7] Lipoprotein(a) and Familial Hypercholesterolemia: A Short Review Including the Laboratory Viewpoint
    Hamasaki, Masato
    Kotani, Kazuhiko
    [J]. CARDIOLOGY RESEARCH, 2020, 11 (06) : 356 - 359
  • [8] The genetics and screening of familial hypercholesterolaemia
    Henderson, Raymond
    O'Kane, Maurice
    McGilligan, Victoria
    Watterson, Steven
    [J]. JOURNAL OF BIOMEDICAL SCIENCE, 2016, 23
  • [9] Hendricks-Sturrup R.M., 2020, J PERS MED, V10
  • [10] The distribution and characteristics of LDL receptor mutations in China: A systematic review
    Jiang, Long
    Sun, Li-Yuan
    Dai, Yan-Fang
    Yang, Shi-Wei
    Zhang, Feng
    Wang, Lu-Ya
    [J]. SCIENTIFIC REPORTS, 2015, 5