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A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Novel LDLR variants affecting low density lipoprotein metabolism identified in familial hypercholesterolemia
Miao Wang1, Ling Hong1, Luyi Cai1
1Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Department of Assisted Reproduction, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
Insights
This study identified two low-density lipoprotein receptor (LDLR) gene variants in a Chinese familial hypercholesterolemia (FH) family. Functional analysis revealed these variants impair cholesterol metabolism, contributing to FH disease.
Area of Science:
- Genetics
- Biochemistry
- Molecular Biology
Background:
- Familial hypercholesterolemia (FH) is an autosomal dominant lipid metabolism disorder.
- Mutations in the low-density lipoprotein receptor (LDLR) gene are a primary cause of FH.
- Genetic identification of FH mutations aids in precise diagnosis and reduces coronary heart disease (CHD) risk.
Purpose of the Study:
- To identify causative gene mutations in a Chinese FH family.
- To elucidate the pathogenicity and mechanism of identified LDLR mutations.
Main Methods:
- Whole exome sequencing was employed to detect variants in an FH patient.
- Site-directed mutagenesis and cell transfection were used to create and study LDLR constructs.
- Functional assays assessed the impact of variants on LDLR activity, including LDL uptake and binding.
Main Results:
- Two LDLR variants, c.1875 C>G (p.N625K; novel) and c.1448G>A (p.W483*), were identified in the Chinese FH family.
- The W483* variant was classified as Pathogenic, and the N625K variant as Variant of Uncertain Significance (VUS) per ACMG guidelines.
- Both variants demonstrated impaired LDL uptake and binding, leading to reduced cholesterol clearance.
Conclusions:
- The study provides novel experimental evidence of functional alterations caused by LDLR variants.
- The findings expand the known spectrum of LDLR mutations associated with FH.
- Understanding these variants aids in the genetic diagnosis and management of FH.
Background:
Familial hypercholesterolemia (FH) is an autosomal dominant disease of lipid metabolism mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Genetic detection of patients with FH help with precise diagnosis and treatment, thus reducing the risk of coronary heart disease (CHD) and other related diseases. The study aimed to identify the causative gene mutations in a Chinese FH family and reveal the pathogenicity and the mechanism of these mutations.
Methods And Results:
Whole exome sequencing was performed in a patient with severe lipid metabolism dysfunction seeking fertility guidance from a Chinese FH family. Two LDLR variants c.1875 C > G (p.N625K; novel variant) and c.1448G > A (p.W483*) were identified in the family. Wildtype and mutant LDLR constructs were established by the site-direct mutagenesis technique. Functional studies were carried out by cell transfection to evaluate the impact of detected variants on LDLR activity. The two variants were proven to affect LDL uptake and binding, resulting in cholesterol clearance reduction to different degrees. According to The American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines, the W483* variant was classified as "Pathogenic", while the N625K variant as "VUS".
Conclusions:
Our results provide novel experimental evidence of functional alteration by LDLR variants identified in our study and expand the mutational spectrum of LDLR mutation induced FH.
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