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Systematic prediction of familial hypercholesterolemia caused by low-density lipoprotein receptor missense mutations

  • Author Footnotes
    1 These authors contributed equally to this work as co-first authors.
    Jiayan Guo
    Footnotes
    1 These authors contributed equally to this work as co-first authors.
    Affiliations
    Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd., Shanghai, China
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  • Author Footnotes
    1 These authors contributed equally to this work as co-first authors.
    Yan Gao
    Footnotes
    1 These authors contributed equally to this work as co-first authors.
    Affiliations
    National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Xun Li
    Affiliations
    Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd., Shanghai, China
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  • Ying He
    Affiliations
    Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd., Shanghai, China
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  • Xin Zheng
    Affiliations
    National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Jianjun Bi
    Affiliations
    Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd., Shanghai, China
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  • Libo Hou
    Affiliations
    National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Yinxi Sa
    Affiliations
    National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Mingqiang Zhang
    Affiliations
    Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd., Shanghai, China
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  • Hong Yin
    Correspondence
    Corresponding author. Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd., 13F, Building 2, 4560 Jinke Road, Shanghai, 201210, China.
    Affiliations
    Amgen Biopharmaceutical Research & Development (Shanghai) Co., Ltd., Shanghai, China
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  • Lixin Jiang
    Correspondence
    Corresponding author. National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Diseases, 167 Beilishi Rd., Beijing, 100037, China.
    Affiliations
    National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work as co-first authors.

      Highlights

      • A total of 13,167 single amino acid missense substitutions in LDLR were modeled, in which 10,490 substitutions predicted FH pathogenicity with functional impact predictions.
      • 52 out of all 54 reported experimentally-tested LDLR variants were consistent with our predictions.
      • Three newly-identified FH-causing LDLR variants in patients and two novel benign variants validated our model predictions experimentally.
      • This is the first to systematically predict pathogenic LDLR single amino acid missense substitutions with corresponding functional characteristics.

      Abstract

      Background and aims

      Familial hypercholesterolemia (FH) is a an autosomal dominant disorder characterized by very high levels of low-density lipoprotein cholesterol (LDL-C). It is estimated that >85% of all FH-causing mutations involve genetic variants in the LDL receptor (LDLR). To date, 795 single amino acid LDLR missense mutations have been reported in the Leiden Open Variation Database (LOVD). However, the functional impact of these variants on the LDLR pathway has received little attention and remains poorly understood. We aim to establish a systematic functional prediction model for LDLR single missense mutations.

      Methods

      Using a combined structural modeling and bioinformatics algorithm, we developed an in silico prediction model called “Structure-based Functional Impact Prediction for Mutation Identification” (SFIP-MutID) for FH with LDLR single missense mutations. We compared the pathogenicity and functional impact predictions of our model to those of other conventional tools with experimentally validated variants, as well as in vitro functional test results for patients with LDLR variants.

      Results

      Our SFIP-MutID model systematically predicted 13,167 potential LDLR single amino acid missense substitutions with biological effects. The functional impact of 52 out of 54 specific mutations with reported in vitro experimental data was predicted correctly. Further functional tests on LDLR variants from patients were also consistent with the prediction of our model.

      Conclusions

      Our LDLR structure-based computational model predicted the pathogenicity of LDLR missense mutations by linking genotypes with LDLR functional phenotypes. Our model complements other prediction tools for variant interpretation and facilitates the precision diagnosis and treatment of FH and atherosclerotic cardiovascular diseases.

      Graphical abstract

      Keywords

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