@misc{10481/57566,
year = {2019},
month = {6},
url = {http://hdl.handle.net/10481/57566},
abstract = {Lecithin-cholesterol acyltransferase (LCAT) is a plasma enzyme that esterifies cholesterol in high- and
low-density lipoproteins (HDL and LDL). Mutations in LCAT gene causes familial LCAT deficiency, which is
characterized by very low plasma HDL-cholesterol levels (Hypoalphalipoproteinemia), corneal opacity and anemia,
among other lipid-related traits. Our aim is to evaluate clinical/biochemical features of a Chilean family with a
proband showing clinical signs of familial LCAT deficiency, as well as to identify and assess the functional effects of
LCAT mutations. LCAT sequencing identified rare p.V333 M and p.M404 V missense mutations in compound heterozygous
state in the proband, as well the common synonymous p.L363 L variant. LCAT protein was detected in proband’s
plasma, but with undetectable enzyme activity compared to control relatives. HEK-293 T transfected cells with
vector expression plasmids containing either p.M404 V or p.V333 M cDNA showed detectable LCAT protein
expression both in supernatants and lysates from cultured cells, but with much lower enzyme activity compared to
cells transfected with the wild-type sequence. Bioinformatic analyses also supported a causal role of such rare
variations in LCAT lack of function. Additionally, the proband carried the minor allele of the synonymous p.L363 L
variant. However, this variant is unlikely to affect the clinical phenotype of the proband given its relatively high
frequency in the Chilean population (4%) and its small putative effect on plasma HDL-cholesterol levels.
Conclusion: Genetic, biochemical, in vitro and in silico analyses indicate that the rare mutations p.M404 V and p.
V333 M in LCAT gene lead to suppression of LCAT enzyme activity and cause clinical features of familial LCAT
deficiency.},
organization = {This work was supported by Proyecto FONDECYT 1150416 and Proyecto
Interdisciplina VRI-PUC II15024 from the Dirección de Investigación, Pontificia
Universidad Católica de Chile. Genotyping of GOCS was performed in the in
the Human Genotyping laboratory at the Spanish National Cancer Research
Centre, a member of CeGen (PRB2-ISCIII), and was supported by grant PT13/
0001/0005 of PE I + D + i 2013-2016 funded by ISCIII and ERDF (Fondo Europeo
de Desarrollo Regional). This research was partially supported by the
supercomputing infrastructure of the NLHPC (ECM-02). L.V. and C.B. were
supported by VRI, Pontificia Universidad Católica de Chile (Proyecto Investigación
Interdisciplinaria VRI-PUC II15024). TG was supported by “Beca de Magíster
Nacional” CONICYT. L.V. was additionally supported by FONDECYT postdoctoral grant 3170038. We express our gratitude to the proband and
relatives.},
publisher = {Springer Nature},
keywords = {Lecithin-cholesterol acyltransferase},
keywords = {HDL-cholesterol},
keywords = {Hypoalphalipoproteinemia},
title = {Identification and functional analysis of missense mutations in the lecithin cholesterol acyltransferase gene in a Chilean patient with hypoalphalipoproteinemia},
doi = {10.1186/s12944-019-1045-0},
author = {Tobar, Hugo and Álvarez Mercado, Ana Isabel and Aguilera García, Concepción María and Gil Hernández, Ángel},
}