Recurrent missense mutations at the first and second base of codon Arg243 in human lipoprotein lipase in patients of different ancestries

Abstract

Mutations in the lipoprotein lipase (LPL) gene are the most common cause of familial chylomicronemia. Here we define the molecular basis of LPL deficiency in four patients of German, French, Dutch, and Chinese descent. We show that two of the probands of Dutch and Chinese origin have a previously described Arg243His mutation while the patients of German and French descent have a novel Arg243Cys substitution in their LPL gene. Haplotype analysis is in favour of two separate origins for the Arg243Cys substitution which together with the Arg243His mutation would implicate three recurrent mutations involving the first and second nucleotides of the codon encoding Arg243 of the LPL gene. The recurrent mutations affecting the first and second nucleotide of CGC coding for the normal Arg residue are support for the high mutability of CpG dinucleotides within the LPL gene.

Lipoprotein Lipase Deficiency (R243H) in a Type 2 Diabetes Patient with Multiple Arterial Aneurysms

“…She had hypertension and type 2 diabetes mellitus (T2DM), both of which had been well controlled since initially being diagnosed. To the best of our knowledge, only two cases with this homozygous missense mutation have been reported, but these patients were too young (23 days and 2 months after birth) for an evaluation of atherosclerosis (6,9). Notably, our present case had developed multiple arterial aneurysms and several atherosclerotic lesions in the coronary and carotid arteries, suggesting that this mutation may thus play a role in atherosclerotic progression.…”

“…It has been proposed that LPL protein lacking any lipase activity may function as a bridge between apoB-containing lipoproteins and proteoglycans on vessel walls, thereby retaining atherogenic lipoproteins on endothelial cells, and leading to the progression of atherosclerosis (7,14). In fact, patients with complete LPL deficiency, whereby both enzymatic activity and protein mass are absent, reportedly exhibit a nonatherogenic phenotype (15,16), while patients with missense mutations which result in the absence of LPL activity with retention of the LPL protein are prone to atherogenesis (4,(6)(7)(8). Therefore, functionally inactive R243H-LPL protein may have played a role in the development of the severe atherosclerosis observed in this patient.…”

“…Considering these observations together, severe hypertriglyceridemia due to LPL However, in contrast to heterozygosity for the LPL gene mutations (11), a complete absence of LPL activity due to homozygous or compound heterozygous mutations has generally been considered to be non-atherogenic (12), because the CM particles, in which triglycerides are not hydrolyzed, are thought not to penetrate the vessel walls due to their large sizes (3). On the other hand, in recent years, several reports have indicated that atherosclerotic diseases do, in fact, develop in patients with some forms of LPL deficiency (4)(5)(6)(7)(8). This issue thus remains controversial.…”

“…On the other hand, it was believed that LPL deficiency does not lead to atherosclerosis development, because CM particles are too large to penetrate the endothelium of the arterial wall (3). However, in recent years, there have been several reports indicating that patients with LPL deficiency do, in fact, show accelerated atherosclerosis (4)(5)(6)(7)(8). Therefore, whether or not hypertriglyceridemia caused by LPL deficiency leads to atherosclerosis remains a controversial topic.…”

Asymptomatic Massive Hypertriglyceridemia in an Octogenarian

“…Type III (1/10 -5 ) is related to an ApoE-linked metabolic defect. Type IV is a common autosomal dominant disease (1/100) due to defective lipolysis [1,2] and/or very-lowdensity lipoprotein (VLDL) overproduction [3]. The phenotypic conversion from type IV to type V (attributable to endocrine or nutritional factors) is common.…”