Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia

• Published in: Atherosclerosis 2011-10, Vol.218 (2), p.391-396
• Main Authors: Vaca, Gerardo, Vàzquez, Alejandra, Magaña, Marìa Teresa, Ramìrez, Marìa Lourdes, Dàvalos, Ingrid P, Martìnez, Esperanza, Marìn, Bertha, Carrillo, Gabriela
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Alleles; Anticholesteremic Agents - pharmacology; APOB gene; Apolipoproteins B - genetics; atherosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular; cholesterol; Cholesterol - metabolism; counseling; DNA Mutational Analysis; Familial hypercholesterolemia; Familial ligand-defective apolipoprotein B100; Family genetic cascade screening; Female; Genotype; heterozygosity; homozygosity; Homozygote; Humans; hypercholesterolemia; Hyperlipoproteinemia Type II - ethnology; Hyperlipoproteinemia Type II - genetics; LDLR gene; low density lipoprotein; Male; Medical sciences; Mexican population; Mexico; Middle Aged; Mutation; Mutations; Phenotype; Pneumology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Receptors, LDL - genetics; Sequence Analysis, DNA
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2011.06.006

The goal of this project was to identify families with autosomal dominant hypercholesterolemia (ADH) to facilitate early detection and treatment and to provide genetic counselling as well as to approximate the mutational diversity of ADH in Mexico. Mutational analysis of the LDLR and APOB genes in 62 index cases with a clinical and/or biochemical diagnosis of ADH was performed. Twenty-five mutations (24 LDLR, 1 APOB) were identified in 38 index cases. A total of 162 individuals with ADH were identified using familial segregation analysis performed in 269 relatives of the index cases. In addition, a novel PCSK9 mutation, c.1850 C>A (p.Ala617Asp), was detected. The LDLR mutations showed the following characteristics: (1) four mutations are novel: c.695 −1G>T, c.1034_1035insA, c.1586 G>A, c.2264_2273del; (2) the most common mutations were c.682 G>A (FH-Mexico), c.1055 G>A (FH-Mexico 2), and c.1090 T>C (FH-Mexico 3); (3) five mutations were identified in 3 or more apparently unrelated probands; (4) three mutations were observed in a true homozygous state; and (5) four index cases were compound heterozygous, and one was a carrier of two mutations in the same allele. These results suggest that, in Mexico, ADH exhibits allelic heterogeneity with 5 relatively common LDLR mutations and that mutations in the APOB gene are not a common cause of ADH. This knowledge is important for the genotype–phenotype correlation and for optimising both cholesterol lowering therapies and mutational analysis protocols. In addition, these data contribute to the understanding of the molecular basis of ADH in Mexico.