Genetic relationship of a Mexican Afromestizo population through the analysis of the 3' haplotype of the beta globin gene in betaA chromosomes.

We analyzed 112 beta(A) chromosomes from the Costa Chica region, with the aim of determining the 3' haplotype (3'Hp) in Afromestizo individuals and its relationship with the reported populations. Thirty polymorphic sites were identified by sequencing and two by restriction fragment length polymorphisms. Genetic variability, genetic distances and neutrality tests were performed with the computer program Arlequin 3.0. Three groups were constructed, which we named 3 kb-Hp, 330 bp-Hp and 2.67 kb-Hp with 32, 15 and 17 polymorphic sites respectively. In 3 kb-Hp, 34 different 3' haplotypes (14 of them new) were found; the three most common were 7B1 (17.8%), 7A1 (17.0%) and 1C1 (14.3%). 330 bp-Hp revealed 18 different allelic sequences; the most frequent were the 1 (AT(9)T(5), 22.3%), 2 (AT(8)T(5), 20.5%) and 3 (AT(7)T(7), 20.5%). 2.67 kb-Hp displayed 14 distinct haplotypes, with B1 (30.3%), A1 (28.6%) and C1 (21.4%) having the highest frequencies. The gene diversity of the Costa Chica population was only significantly different to Gambia. In the genetic distances, the p values were not significant for Vanuatu, Sumatra and Central African Republic. The neutrality tests showed that the patterns of diversity in the Costa Chica population deviate significantly from the expectations of the standard neutral model. This is the first work performed in Mexico in which the extended 3'Hp was analyzed in beta(A) chromosomes. The study showed clearly the presence of African and Asian genes in the Costa Chica population.

Prevalence of -alpha(3.7) and alpha alpha alpha(anti3.7) alleles in sickle cell trait and beta-thalassemia patients in Mexico.

The aim of this study was to determine the frequency of alpha-globin gene mutations in three groups of Mexican unrelated individuals. The first two groups were normal and sickle cell trait individuals from the Costa Chica region, a place with a 12.8% frequency of HbS carriers, and the third group comprised of Mexican mestizo patients with beta-thalassemia. We searched for -alpha(3.7) and -alpha(4.2) alpha(+)-thalassemia deletion alleles, as well as the alpha alpha alpha(anti3.7) triplication through long-gap PCR. The alleles -alpha(3.7) and alpha alpha alpha(anti3.7) were found in the heterozygote state only; 19% of the normal subjects had the -alpha(3.7) allele, and 2% showed the alpha alpha alpha(anti3.7) allele. In individuals with the sickle cell trait, 17% had the -alpha(3.7) deletion, and the alpha alpha alpha(anti3.7) triplication was observed in 3% of these individuals. We revealed that 16% of the subjects with beta-thalassemia showed the -alpha(3.7) deletion and 28% the alpha alpha alpha(anti3.7) triplication. The -alpha(4.2) deletion was not detected in any individual. The frequency of the -alpha(3.7) allele was roughly the same in the three groups studied; this can be explained by the fact that the three groups have common genes from Africa and the Mediterranean, where a high prevalence of alpha(+)-thalassemia has been observed. To our knowledge, the frequency of alpha alpha alpha(anti3.7) triplication observed in the Mexican beta-thalassemia patients is the highest reported. As the -alpha(3.7) and alpha alpha alpha(anti3.7) alleles are very common in our selected populations, we believe that there is a need to investigate systematically the alpha-globin gene mutations in all hemoglobinopathies in the Mexican population.

3' haplotypes of the beta-globin gene in beta(S)-chromosomes of Mexican individuals.

The beta-globin gene cluster has shown high polymorphic diversity organized in 5' and 3' haplotypes (Hps). beta(S)-Chromosomes are in linkage disequilibrium with the 5' Hps Bantu, Benin, Senegal, Cameroon, and Arab-Indian. In Mexican mestizos with African west coast origins, we observed the following 5' Hps in beta(S)-chromosomes: Bantu, 78.8%; Benin, 18.2%; and atypical Hp 9, 3.0%. With the purpose of establishing the 3' Hps, we analyzed 35 polymorphic sites--6 by RFLP analysis and 29 by DNA sequencing--in 33 unrelated beta(S)-chromosomes. The polymorphic sites were structured according to Harding et al. [R.M. Harding, S.M. Fullerton, R.C. Griffiths, J.B. Clegg, Archaic African and Asian lineages in the genetic ancestry of modern humans, Am. J. Hum. Genet. 60 (1997) 772-789] and Lapoumeroulie et al. [C. Lapoumeroulie, O. Dunda, R. Ducrocq, G. Trabuchet, M. Mony-Lobe, J.M. Bodo, P. Carnevale, D. Labie, J. Elion, R. Krishnamoorthy, A novel sickle cell mutation of yet another origin in Africa: the Cameroon type, Hum. Genet. 89 (1992) 333-337]. All Bantu beta(S)-chromosomes showed the 12A1 3' Hp with (AT)6T9 repeats (84.9%), a novel 3' Hp. The Benin Hp was 2B2, with (AT)8T4 (12.1%), and the atypical Hp 9 4B1, (AT)8T5 (3.0%). Because of the high linkage disequilibrium observed for the Bantu and 12A1 Hps, we expect that, if there is a single origin of the Bantu beta(S) mutation, all must show the 12A1 polymorphic DNA sequence in the 3' Hp. A correlation between the 5' and 3' Hps could be observed with the other beta(S) mutations. The atypical Hp 9 was also atypical at the 3' Hp, with the same repeats as observed with the Cameroon beta(S) mutation; however, it differed in one position from the typical Lapoumeroulie Cameroon Hp, indicating that these beta(S)-chromosomes arose by different genetic mechanisms or by a novel beta(S) mutation. We stress the importance of the study of DNA polymorphisms at 3' Hp to allow understanding of the genetic diversity of beta(S)-chromosomes, as well as their implications in beta(S) gene expression and the possible effects on the clinical phenotype.

Molecular spectrum of beta-thalassemia in the Mexican population.

Beta-thalassemia (beta-thal) is present in 59% and 75% of patients with abnormal hemoglobin disorders in northwestern and central Mexico, respectively. In our Research Center, up until 1997, we reported the presence of 13 beta-thal alleles in 26 unrelated chromosomes (-28A>C; -87C>T; MET1VAL; IVS1, G>A, +1; IVS1, G>A, +5; IVS1, G>C, +5; IVS1, G>A, +110; IVS2, C>G, +745; GLU6FS; VAL11FS; GLN39TER; HBD/HBB 104 kb del; and HBD87/HBB116 fusion). Since then, 57 more beta-thal chromosomes have been identified by the amplification-refractory mutation system (ARMS) and DNA sequencing from 54 individuals with beta-thalassemia (seven compound heterozygotes, three with two beta-thal alleles, three with beta-thal and HbS, and one with beta-thal and HbD; and 47 beta-thal heterozygotes). Nine of the previously observed alleles were found, together with three new alleles: IVS2, G>A, +1; LYS17TER; and 4-bp del, 41/42CTTT. Moreover, a novel mutation was observed, HIS77FS, bringing to a total of 17 beta-thal alleles identified in our population. Six alleles constitute 78.3% of the observed alleles: five Mediterranean alleles (GLN39TER; IVS1, G>A, +1; IVS1, G>A, +110; HBD/HBB 104 kb del; and IVS1, G>A, +5) and one common in the Kurdish population (-28A>C). We note especially the presence in these families of -28A>C and VAL11FS, both of which have previously been considered private alleles. The observed spectrum of mutations is characteristic of populations with low frequencies of thalassemias. Because thalassemia is not a rare disease in Mexico, we emphasize its necessary consideration in the differential diagnosis of microcytic hypochromic anemia.

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.

Analysis of betaS and betaA genes in a Mexican population with African roots.

To investigate the origin of the beta(A) and beta(S) genes in a Mexican population with African roots and a high frequency of hemoglobin S, we analyzed 467 individuals (288 unrelated) from different towns in the states of Guerrero and Oaxaca in the Costa Chica region. The frequency of the sickle-cell trait was 12.8%, which may represent a public health problem. The frequencies of the beta-haplotypes were determined from 350 nonrelated chromosomes (313 beta(A) and 37 beta(S)). We observed 15 different beta(A) haplotypes, the most common of which were haplotypes 1 (48.9%), 2 (13.4%), and 3 (13.4%). The calculation of pairwise distributions and Nei's genetic distance analysis using 32 worldwide populations showed that the beta(A) genes are more closely related to those of Mexican Mestizos and North Africans. Bantu and Benin haplotypes and haplotype 9 were related to the beta(S) genes, with frequencies of 78.8, 18.2, and 3.0%, respectively. Comparison of these haplotypes with 17 other populations revealed a high similitude with the population of the Central African Republic. These data suggest distinct origins for the beta(A) and beta(S) genes in Mexican individuals from the Costa Chica region.

Hb Lepore Washington-Boston in two Mexican mestizo families

Se describen dos familias mestizas mexicanas con Hb lepore Washington-Boston: una familia es de Córdova en el estado de Veracruz, ubicado en la costa del este de México en la cual el caso índice es un varón asintomático de 44 años de edad con ancestros italianos; la otra es una nativa de Durango, en el noreste del país, en que el caso es una mujer embarazada de 32 años de edad con ancestros franceses. En ambos casos la Hb leporese identificó por electroforesis alcalina y se caracterizó por cromatografía líquida de alta resolución y PCR con oligonucleótidos específicos flanqueando el marco de la deleción. El haplotipo en ambas familias fue +----++, que es el haplotipo ß más comúnmente reportado con esta mutación. Estos son los primeros casos de esta entidad de México

Alelos talasémicos en mestizos mexicanos / Thalassemia aleles in Mexicans mestizos

Se presenta un análisis de los alelos talasémicos observados en mestizos mexicanos: En 18 pacientes no emparentados con anemia hemolítica de moderada a severa (16 con ß-tal y 2 con Ó-tal), se identificaron 25 cromosomas con 14 alelos diferentes (10 para ß-tal) con predominio de alelos del Mediterráneo (7 ß-tal y 2 Ó-tal). La mutación más común fue la sin sentido Cd 39, observada en siete cromosomas (28 por ciento); se observaron, además tres alelos asiáticos, uno ß-tal hindú (l-1 nt 5 GÄC), dos del sureste de Asia (Ä SEA Y ÄFIL), uno originario de judíos curdos (-28 AÄC) y uno mexicano (Cd 11-T), lo que muestra una heterogeneidad molecular alta en nuestra población