Ile225Thr loop mutation in thelipoprotein lipase (LPL) gene is a de novo event

Abstract

Mutations in the lipoprotein lipase (LPL) gene are the most important cause of familial chylomicronemia with over 70 mutations being recorded to date. Thus far de novo mutations have not been described. Here we report on the molecular analysis of the family of a patient previously reported to be LPL deficient on the basis of compound heterozygosity for the Arg243His and Ile225Thr mutations, the latter being the first and only mutation identified in the loop region of LPL. Both parents of the propositus were screened for the presence of these two mutations to confirm their status as obligate heterozygotes and to determine the mutation allocation. Although paternal inheritance of the Arg243His allele could be established, maternal DNA did not show carrier status for the Ile225Thr substitution. An examination of maternity, using LPL restriction fragment length polymorphisms four polymorphic CA repeats and ApoE genotypes, was consistent with correct biological parentage for the propositus. Therefore, we conclude that the Ile225Thr mutation constitutes a de novo event, the first to be reported in the LPL gene.

Significant but partial lipoprotein lipase functional loss caused by a novel occurrence of rare LPL biallelic variants

“…Furthermore, p.Arg270His had been previously reported in the literature [ 19 – 23 ] and is documented in the ClinVar database [ 24 ]. This variant was consistently identified in patients with classical FCS, whether in a homozygous or compound heterozygous state [ 19 – 23 ].…”

“…Furthermore, p.Arg270His had been previously reported in the literature [ 19 – 23 ] and is documented in the ClinVar database [ 24 ]. This variant was consistently identified in patients with classical FCS, whether in a homozygous or compound heterozygous state [ 19 – 23 ]. Notably, the first three reports conducted in vitro functional characterizations of the p.Arg270His variant and consistently found no LPL activity in the medium of the transfected cells [ 19 – 21 ].…”

Causes, clinical findings and therapeutic options in chylomicronemia syndrome, a special form of hypertriglyceridemia

“…More than 90% of monogenic chylomicronemia is due to mutations in the LPL gene [25]. Indeed, more than 114 LPL gene mutations have been described so far [25,26,[48][49][50][51][52][53][54][55]. Other mutations influencing LPL activity are much less common, such as mutations in the genes of the regulators of LPL including apoC2, apoA5, LMF-1, and GPIHBP1 [28,42].…”

Characterizing familial chylomicronemia syndrome: Baseline data of the APPROACH study

“…More than 180 pathogenic mutations have been described in the LPL gene, with some mutations clustering regionally secondary to founder effects. [8][9][10][11][12][13] Apolipoprotein C-II is an essential activator of LPL and bi-allelic mutations in the APOC2 gene leads to functional LPL deficiency and phenotypic FCS. 5,[14][15][16] Apolipoprotein A-V also enhances the activity of LPL, and rare mutations in the APOA5 gene have been described as causing FCS, although penetrance is often incomplete and hypertriglyceridemia may be noted only later in life.…”