Abstract—Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the three known genes. Low density lipoprotein receptor (LDLR) is considered as main contributor. We recruited clinically diagnosed 21 hypercholesterolemia families from Punjab-Pakistan. High resolution melting analysis used to screen the LDLR gene (all exons and promoter region) and variations were confirmed by restriction fragment length polymorphism and sequencing analysis. The mean of total cholesterol and LDL-cholesterol in the FH patients was 7.5±1.4mmol/l and 5.2±1.5mmol/l respectively. Seven patients showed synonymous variations in the sequence at position c.81T>C, c.993C>T, c.1413G>A, c.1617C>T, c.1725C>.T, c.1959T>C and c.2232A>G while one carried the non-synonymous change c.1171G>A resulting in the non-pathogenic p.(A391T) amino acid change. One common non-pathogenic variant c.1060+10C>G was found in the intronic region. In-silico analysis predicted c.1725C>T, c.1959T>C and c.2232A>G to be affecting the LDLR protein, by altering splicing sites as predicted by Human Splicing Finder and Mutation Taster software. Our findings suggest that ~15% (3/21) of FH patients in Pakistan with no detectable mis-sense mutation may carry pathogenic splicing variants in the LDLR gene sequence.

Index Terms—LDL-cholesterol, synonymous, polymorphic, splicing site

Cite:Akhtar Ali, Ros Whittall, Masroor Ellahi Babar, Tanveer Hussain, and Steve E. Humphries, "Genetics of LDLR Gene in Pakistani Hypercholesterolemia Families," International Journal of Pharma Medicine and Biological Sciences, Vol. 8, No. 4, pp. 143-146, October 2019. doi: 10.18178/ijpmbs.8.4.143-146