María Teresa Magaña

Red cell membrane protein deficiencies in Mexican patients with hereditary spherocytosis

Twenty-seven families and four individual patients with hereditary spherocytosis (HS) from the northwestern region of Mexico were studied. An autosomal dominant inheritance pattern was identified in 59% of 22 families. Densitometric analysis of erythrocyte membrane proteins revealed individual protein deficiencies in 39% of the patients studied, in whom the principal altered proteins were the alpha spectrins (13%), band 3 protein (10%), ankyrin (6%), 4.2 protein (6%), and the beta spectrins (3%). A predominant deficiency of spectrins has also been observed in other Latin American and Mediterranean countries. However, it is well known that deficiencies in these proteins are heterogeneous across different ethnic groups. A combined protein deficiency was observed in 52% of patients, most frequently involving the spectrins, band 3 protein, 4.2 protein, and 4.1 protein. In three subjects, no abnormalities were detected (10%). We conclude that, despite the observed heterogeneity, the principal affected proteins are essentially similar to those observed in other ethnic groups.

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

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.

Diversity of the 5′ β-Globin Haplotype of Four β-Thalassemia Mutations in the Mexican Population

β-Globin haplotypes have been used to investigate the origin and spread of β-globin mutations such as Hb S [β6(A3)Glu→Val, GAG>GTG], Hb E [β26(B8)Glu→Lys, GAG>AAG], and β-thalassemia (β-thal). Molecular analyses revealed the presence of 17 β-thal mutations in the Mexican population; the most frequent of these are the nonsense codon 39 (C>T), IVS-I-1 (G>A), IVS-I-110 (G>A), and −28 (A>C). To improve our knowledge about their origin, we analyzed the 5′ haplotypes by restriction fragment length polymorphism. The codon 39 mutation (n = 17) was observed with five 5′ haplotypes: 1 (59%), 2 (23%), and 4, 6, and 9 (6% each). The IVS-I-1 mutation (n = 15) was found with five 5′ haplotypes: 1 (73.6%), 2, 3, 5, and 11 (6.6% each), whereas the IVS-I-110 (n = 9) and −28 mutations (n = 1) were only associated with haplotype 1. In the population studied, the codon 39 and IVS-I-1 mutations show a multicentric origin, whereas the IVS-I-110 and −28 mutations have an apparent single origin. Further investigation is required for the analysis of the polymorphisms surrounding the β-globin gene.

Linkage disequilibrium between four MTTP gene polymorphisms in a Mexican population.

Background: The microsomal triglyceride transfer protein plays an important role in the folding, assembling and secretion of lipoproteins that contain apoprotein B. Different polymorphisms in the MTTP gene have been associated with risk factors for coronary heart disease and diabetes, the first and fourth most common causes of death in Mexico, respectively. Aim: The objective of this study was to assess allele, genotype and haplotype frequencies of six MTTP polymorphisms in an unselected Mexican population. Subjects and methods: Six polymorphisms were analysed by DNA sequencing of polymerase chain reaction products in 155 Mexican individuals and Hardy–Weinberg equilibrium, genetic variability, linkage disequilibrium and neutrality test were evaluated. Results: The rare alleles of the six polymorphisms analysed had frequencies greater than 1% and their genotype distributions were in accordance with Hardy–Weinberg equilibrium. All three promoter and I/T 128 polymorphisms were in linkage disequilibrium. Twelve different haplotypes were observed; GATGGT (70.44%) and TTCGGC (13.91%) were the most common. Diversity patterns in this Mexican population deviate significantly from expectations of the standard neutral model for infinite allele. Conclusion: The −493 G/T, −400 A/T, −164 T/C and I/T 128 polymorphisms can be useful for association studies in this population.