Mutation analysis reveals an insertional hotspot in exon 4 of the LDL receptor gene

Abstract

Mutation analysis of the low density lipoprotein receptor (LDLR) gene revealed a novel 8-bp duplication after nucleotide 681 in a Costa Rican patient with familial hypercholesterolaemia. The frameshift caused by this mutation results in a premature termination codon in the EGF precursor homology domain of the mature LDLR, whereby a truncated protein of the first 206 residues with an additional 39 abnormal residues would be created. The insertion overlaps with previously described duplications of 18 bp and 21 bp, thus revealing an insertional hotspot in exon 4 of the LDLR gene. We propose that the structural features of this region of the LDLR gene contribute significantly to genetic instability and the subsequent DNA duplication via an endogenous sequence-directed mechanism of mutagenesis.

Missense Mutation in the LDLR Gene: A Wide Spectrum in the Severity of Familial Hypercholesterolemia

“…In the LDLR gene sequence, this consensus is present at the 3' end of exon 4 at position c.681-687. Among the 96 deletions (in frame and frameshift) in the LDLR gene, 11 (11.5%) are at this position pointing to a discrete hot spot for insertions, as observed in Figure 2 and in accordance with previous reports (Kotze et al 1996).…”

Phenotypic variation and genetic polymorphism of low-density lipoprotein exon 4 receptor gene among Jordanian familial hypercholesterolemia patients

“…Exon 4B was amplified by mixing 0.1 mM MgCl 2 , 1X MgCl 2 -free buffer, 0.05 mM of PCR nucleotides mix, 1.1 nmol of primer 1, 2.0 nmol of primer 2, 5 units of DNA polymerase, 2 µl of DNA and 15 µl of nuclease-free water. The thermal cycler was programmed as described by [2], except that the annealing temperature was set at 60 °C: one cycle of 96 °C for 10 min, 60 °C for 1 min and 72 °C for 2 min, 35 cycles of 92 °C for 1 min, 59 °C for 1 min and 72 °C for 2 min, and finally one cycle of 72 °C for 2 min.…”

“…FH is recognized clinically by an extreme elevation of LDL-Chol, which is characterized by autosomal dominant or co-dominant transmission. A FH patient may also develop tendon xanthomas, skin xanthomas and coronary heart diseases (CHD); however, some FH patients develop no xanthomas or CHD (1,2). FH genetic defects are classified as defects in LDLR, apolipoprotein B, proprotein convertase subtilisin / kexin type 9 and autosomal recessive hypercholesterolemia gene (3).…”

Two novel and two known low-density lipoprotein receptor gene mutations in German patients with familial hypercholesterolemia

“…In patient D.H. a guanine was found to be inserted after nucleotide 557 at codon 165 in exon 4 of the LDLR gene, a region previously shown to be particularly mutation prone (Hobbs et al, 1992; Kotze et al, 1996). This novel 1-bp insertion alters the reading frame and creates a stop codon at a site corresponding to amino acid residue 174 and would result in a nonfunctional truncated protein (Hobbs et al, 1992).…”