Key result
LDLR c.2160delC variant causes LDLR loss of function via premature transcription termination and defective protein accumulation.
Why the study?
Although many mutations have been reported in familial hypercholesterolemia, only a few have been identified as pathogenic, leaving the pathogenicity of the LDLR c.2160delC variant to be confirmed.
Observational (n=6)
p-value: p=<0.01
The identification and in vitro characterization of the LDLR c.2160delC variant expands the genetic mutation spectrum of familial hypercholesterolemia, confirming its pathogenic role through impaired LDLR trafficking and function.
BACKGROUND: Familial hypercholesterolemia (FH) is an inherited disorder with markedly elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. Although many mutations have been reported in FH, only a few have been identified as pathogenic mutations. This study aimed to confirm the pathogenicity of the LDL receptor (LDLR) c.2160delC variant in FH. METHODS: In this study, the proband and her family members were systematically investigated, and a pedigree map was drawn. High-throughput whole-exome sequencing was used to explore the variants in this family. Next, quantitative polymerase chain reaction (qPCR), western blot (WB) assays, and flow cytometry were conducted to detect the effect of the LDLR c.2160delC variant on its expression. The LDL uptake capacity and cell localization of LDLR variants were analyzed by confocal microscopy. RESULTS: According to Dutch Lipid Clinic Network (DLCN) diagnostic criteria, three FH patients were identified with the LDLR c.2160delC variant in this family. An in-silico analysis suggested that the deletion mutation at the 2160 site of LDLR causes a termination mutation. The results of qPCR and WB verified that the LDLR c.2160delC variant led to early termination of LDLR gene transcription. Furthermore, the LDLR c.2160delC variant caused LDLR to accumulate in the endoplasmic reticulum, preventing it from reaching the cell surface and internalizing LDL. CONCLUSIONS: The LDLR c.2160delC variant is a terminating mutation that plays a pathogenic role in FH.
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Lin et al. (2023) conducted an observational in Familial hypercholesterolemia (n=6). LDLR c.2160delC variant vs. Wild-type LDLR (in vitro) was evaluated on LDLR mRNA and protein expression, and cell surface localization (p=<0.01). The LDLR c.2160delC variant causes premature transcription termination and accumulation of the defective protein in the endoplasmic reticulum, leading to loss of LDLR function and pathogenicity in familial hypercholesterolemia.
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