Familial LCAT Deficiency and Low HDL-C Levels: In silico Characterization of Two Rare LCAT Missense Mutations

Abstract

Mutations in the lecithin-cholesterol acyltransferase (LCAT) gene, which catalyzes the esterification of cholesterol, result in two types of autosomal recessive disorders: Familial LCAT deficiency (FLD) and Fish Eye Disease (FED). While both phenotypes are characterized by corneal opacities and different forms of dyslipidemia, such as low levels of high-density lipoprotein-cholesterol (HDL-C), FLD exhibits more severe clinical manifestations like splenomegaly, anemia, and renal failure. We describe the first clinically and genetically confirmed case of FLD in Colombia which corresponds to a 46-year-old woman with corneal opacity, hypothyroidism, and dyslipidemia, who does not have any manifestations of renal failure, with two pathogenic heterozygous missense variants in the LCAT gene: LCAT (NM_000229.2):c.803G>A (p.Arg268His) and LCAT (NM_000229.2):c.368G>C (p.Arg123Pro). In silico analysis of the mutations predicted the physicochemical properties of the mutated protein, causing instability and potentially decreased LCAT function. These compound mutations highlight the clinical heterogeneity of the phenotypes associated with LCAT gene mutations.

Keywords: LCAT; LCAT deficiency; VLDL; alpha-LCAT deficiency; cholesterol/trafficking; eye; fish eye disease; genomics; lecithin cholesterol acyltransferase deficiency.

Figure 1

Patient´s corneal opacity.

Figure 2

Temporal record of the patient’s HDL-C levels. Red line corresponds to the minimum value of the clinical reference.

Figure 3

Pedigree information of the patient and Sanger sequencing electropherogram of both patient and her family.

Figure 4

Visualization through PyMOL of the crystal structure of the human Lecithin-Cholesterol Acyltransferase (4X96 Protein Data Bank) reported by Glukhova et al 2015. Protein Data Bank accession number 4X96. Arginine residue 123 is visualized in blue and the purple residue corresponds to Arginine 268.