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

Abstract

Sebastian Ciro Acosta,1 Lorena Díaz-Ordóñez,1,2 Juan David Gutierrez-Medina,1,3 Yisther Katherine Silva-Cuero,1,2 Luis Guillermo Arango-Vélez,4,5 Andrés Octavio García-Trujillo,4,5 Harry Pachajoa1,2,6 1Centro de Investigaciones en Anomalias Congenitas y Enfermedades Raras (CIACER), Universidad Icesi, Cali, Colombia; 2Departamento de Ciencias Basicas Medicas, Facultad de Salud, Universidad Icesi, Cali, Colombia; 3Centro de Investigaciones Clinicas, Fundacion Valle del Lili, Cali, Colombia; 4Servicio de Endocrinologia, Fundacion Valle del Lili, Cali, Colombia; 5Departamento de Medicina interna, Seccion de Endocrinologia, Universidad Icesi, Cali, Colombia; 6Genetic Division, Fundacion Valle del Lili, Cali, ColombiaCorrespondence: Lorena Díaz-Ordóñez, Centro de Investigaciones en Anomalias Congenitas y Enfermedades Raras (CIACER), Universidad Icesi, Street 18 Number 122-135, Cali, Valle del Cauca, 760031, Colombia, Tel [phone], Email [email protected]: 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: eye, LCAT, cholesterol/trafficking, genomics, VLDL, lecithin cholesterol acyltransferase deficiency, LCAT deficiency, alpha-LCAT deficiency, fish eye disease

Keywords

• eye
• lcat
• cholesterol/trafficking
• genomics
• vldl
• lecithin cholesterol acyltransferase deficiency
• lcat deficiency
• alpha-lcat deficiency
• fish eye disease.