Novel and recurrent LDLR gene mutations in Pakistani hypercholesterolemia patients

Abstract

The majority of patients with the autosomal dominant disorder familial hypercholesterolemia (FH) carry novel mutations in the low density lipoprotein receptor (LDLR) that is involved in cholesterol regulation. In different populations the spectrum of mutations identified is quite different and to date there have been only a few reports of the spectrum of mutations in FH patients from Pakistan. In order to identify the causative LDLR variants the gene was sequenced in a Pakistani FH family, while high resolution melting analysis followed by sequencing was performed in a panel of 27 unrelated sporadic hypercholesterolemia patients. In the family a novel missense variant (c.1916T > G, p.(V639G)) in exon 13 of LDLR was identified in the proband. The segregation of the identified nucleotide change in the family and carrier status screening in a group of 100 healthy subjects was done using restriction fragment length polymorphism analysis. All affected members of the FH family carried the variant and none of the non-affected members nor any of the healthy subjects. In one of the sporadic cases, two sequence changes were detected in exon 9, one of these was a recurrent missense variant (c.1211C > T; p.T404I), while the other was a novel substitution mutation (c.1214 A > C; N405T). In order to define the allelic status of this double heterozygous individual, PCR amplified fragments were cloned and sequenced, which identified that both changes occurred on the same allele. In silico tools (PolyPhen and SIFT) were used to predict the effect of the variants on the protein structure, which predicted both of these variants to have deleterious effect. These findings support the view that there will be a novel spectrum of mutations causing FH in patients with hypercholesterolaemia from Pakistan.

Decreased serum PON1 arylesterase activity in familial hypercholesterolemia patients with a mutated LDLR gene

“…Functional mutations in LDLR gene cause the monogenic form of familial hypercholesterolemia (FH) ( Diakou et al , 2011 ; Ahmed et al , 2012 ). Recently, it was also shown that increased serum paraoxonase activity in LDLR (-/-) mice significantly inhibits progression of atherosclerosis ( Leckey et al , 2010 ).…”

An association study between genetic polymorphisms related to lipoprotein-associated phospholipase A2 and coronary heart disease

“…LDLR mutations often cause autosomal dominant hypercholesterolemia (ADH) by affecting the hepatic clearance of blood LDL-C (40), Notably, ADH is clinically characterized by high blood LDL-C and atherosclerosis that may eventually lead to CHD (41). The majority of Lp-PLA 2 is attached to LDL; however, the known genetic determinants of LDL-C levels, including the LDLR locus, are not significantly associated with CHD.…”

The genetic spectrum of familial hypercholesterolemia in Pakistan

“…We have previously reported the identification of mutations in four different patients from Pakistan, two nonsense mutations, p.(Val806GlyfsX11) [16] and p.(C296X) [17] and three missense mutations p.(R88S) [17], p.(V639G) and p.(T404I)/p. (N405T), which are on the same allele [18]. Here we extend the study to 11 additional probands and their extended families.…”