Genetic Analysis of β-Thalassemia Major and β-Thalassemia Intermedia in Brazil

Abstract

The development of methodologies to identify the molecular lesions responsible for different types of beta-thalassemia has made it possible to correlate these data with clinical and hematological severity. We examined DNA from 35 patients with beta-thalassemia, residents of the State of São Paulo, Brazil, for some types of genetic modifying factors: beta-thalassemia mutations, the upstream Xmnl GY-globin gene polymorphisms, and alpha-globin gene deletions. Additionally, the beta-like gene cluster haplotypes and the presence of the AYT variant were studied. The following mutations were present in the 70 chromosomes studied: 54.3% codon 39 (C-->T) (beta degree); 18.6% IVS-I-6 (T-->C) (beta+); 18.6% IVS-I-110 (G-->A) (beta+), and 4.3% IVS-I-1 (G-->T) (beta degree). Haplotype II was associated with the nonsense mutation at codon 39, haplotype I with the IVS-I-110 and codon 39 mutations, and haplotypes VI and VII with the IVS-I-6 mutation. The Xmnl polymorphism was detected in three out of 31 patients studied. No alpha-thalassemia was detected among the thalassemia intermedia patients. The AYT variant was present in 87.1% of 31 thalassemia patients and was associated with the codon 39/haplotype II and IVS-I-6/haplotype VI mutations. This is the first study of the Brazilian population that has analyzed the beta-thalassemia mutations and other molecular variants, and has correlated them with the clinical manifestations.

A Different Molecular Pattern of β‐Thalassemia Mutations in Northeast Brazil

“…Data obtained in two studies performed in southeast Brazil showed that the most prevalent molecular defect was b 0 -thal owing to the nonsense mutation at codon 39 (C ! T) (8,9). Accordingly, most of the symptomatic patients exhibit a picture of severe transfusion-dependent b-thal major, whereas thalassemia intermedia is very rare (9).…”

“…T) (8,9). Accordingly, most of the symptomatic patients exhibit a picture of severe transfusion-dependent b-thal major, whereas thalassemia intermedia is very rare (9). Similarly, Hb S=b-thal double heterozygotes have a severe sickle cell syndrome, quite similar to homozygous sickle cell anemia (8).…”

Camperdown hemoglobin associated with beta° thalassemia in a Brazilian child

“…The propositus and his mother were found to be heterozygous for a nonsense mutation: the C ® T substitution at the first nucleotide position of the 39 th codon, in exon 2 of the b-globin gene, creates a stop codon resulting in premature termination of the globin chain synthesis. This b-thalassemia mutation is common in the Mediterranean population and is also one of the most frequent b-globin mutations found in Brazil (Fonseca et al, 1998). Another b-globin gene mutation was detected in the propositus and his father: the b104 (G6) arginine residue was replaced by serine [beta 104(G6) Arg ® Ser], resulting in the variant Camperdown Hemoglobin (Hb Camperdown).…”

“…Although data on the extent of the diversity of hemoglobin disorders in Brazil are incomplete (Old, 2003;Zago and Costa, 1985;Fonseca et al, 1998;Araújo et al, 2003), many b-globin mutant alleles have been detected in patients from different Brazilian regions (Araújo et al, 2003;Fonseca et al, 1998;Grignoli et al, 2000).…”

“…Currently, almost 200 different mutations have been described which cause beta-globin imbalance, leading to anemia of variable severity (Fonseca et al, 1998;Olivieri, 1999). The association of thalassemia and structural hemoglobin variants produces a wide spectrum of clinical and hematological outcomes, ranging from severe to moderate microcytic hypochromic anemia to no significant clinical alterations (Olivieri, 1999).…”