Abstract
Familial hypercholesterolemia (FH) is an autosomal dominant disease, predominantly caused by variants in the low-density lipoprotein (LDL) receptor gene (LDLR). Herein, we describe genetic analysis of severely affected homozygous FH patients who were mostly resistant to statin therapy and were managed on an apheresis program. We identified a recurrent frameshift mutation p.(G676Afs*33) in exon 14 of the LDLR gene in 9 probands and their relatives in an apparently unrelated Saudi families. We also describe a three dimensional homology model of the LDL receptor protein (LDLR) structure and examine the consequence of the frameshift mutation p.(G676Afs*33), as this could affect the LDLR structure in a region involved in dimer formation, and protein stability. This finding of a recurrent mutation causing FH in the Saudi population could serve to develop a rapid genetic screening procedure for FH, and the 3D-structure analysis of the mutant LDLR, may provide tools to develop a mechanistic model of the LDLR function.
•We describe severely affected homozygous FH patients who were managed on an LDL-apheresis program.•We identified a recurrent frameshift mutation p.(G676Afs*33) in LDLR gene in 9 probands and their relatives.•Identified mutation could affect the LDLR structure in a region involved in dimer formation, and protein stability.•A recurrent mutation causing FH in the Saudi population could serve to develop a rapid genetic screening procedure for FH.•The 3D-structure analysis of the mutant LDLR may provide tools to develop a mechanistic model of the LDLR function.