Key result
The LDLR c.415G>A mutation causes familial hypercholesterolemia by significantly reducing the capacity of LDLR to bind to LDL, resulting in impaired LDL uptake.
Why the study?
Familial hypercholesterolemia is a prevalent hereditary disease causing aberrant cholesterol metabolism, prompting investigation of the LDLR c.415G>A candidate mutation.
The LDLR c.415G>A mutation is a pathogenic variant that causes familial hypercholesterolemia by impairing LDL binding and uptake.
Background Familial hypercholesterolemia (FH) is a prevalent hereditary disease that can cause aberrant cholesterol metabolism. In this study, we confirmed that c.415G > A in LDLR, an FH-related gene, is a deleterious mutation in FH by in silico analysis and functional experiments. Methods The proband and his family were evaluated by the diagnostic criteria of the Dutch Lipid Clinic Network. Whole-exome and Sanger sequencing were used to explore and validate FH-related mutations. In silico analyses were used to evaluate the pathogenicity of the candidate mutation and its impact on protein stability. Molecular and biochemical methods were performed to examine the effects of the LDLR c.415G > A mutation in vitro. Results Four of six participants had a diagnosis of FH according to the Dutch Lipid Clinic Network. The LDLR c.415G > A mutation in the family was predicted to be pathogenic. qPCR and western blotting suggested that LDLR c.415G > A does not affect the expression of LDLR. Functional studies showed that this mutation may lead to dyslipidemia by impairing the binding and absorption of LDLR to LDL. Conclusion LDLR c.415G > A is a pathogenic mutation in FH; it causes a significant reduction in LDLR's capacity to bind LDL, resulting in impaired LDL uptake. These findings expand the spectrum of mutations associated with FH.
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Wang et al. (2024) studied Familial hypercholesterolemia (n=6). LDLR c.415G>A mutation vs. Wild-type LDLR was evaluated on LDL uptake and LDLR binding capacity. The LDLR c.415G>A mutation causes familial hypercholesterolemia by significantly reducing the capacity of LDLR to bind to LDL, resulting in impaired LDL uptake.
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