Abstract
Alpha thalassemia is the most common genetic disorder across the world, being the α-3.7 deletion the most frequent mutation. In order to analyze the spectrum and origin of alpha thalassemia mutations in Uruguay, we obtained a sample of 168 unrelated outpatients with normal hemoglobin levels with microcytosis and hypochromia from two cities: Montevideo and Salto. The presence of α-thalassemia mutations was investigated by gap-PCR, restriction endonucleases analysis and HBA2 and HBA1 genes sequencing, whereas the alpha-MRE haplotypes were investigated by sequencing. We found 55 individuals (32.7%) with α-thalassemia mutations, 51(30.4%) carrying the -α3.7 deletion, one with the -α4.2 deletion and three having the rare punctual mutation HBA2:c.-59C>T. Regarding alpha-MRE analysis, we observed a significant higher frequency of haplotype D, characteristic of African populations, in the sample with the -α3.7 deletion. These results show that α-thalassemia mutations are an important determinant of microcytosis and hypochromia in Uruguayan patients with microcytosis and hypochromia without anemia, mainly due to the -α3.7 deletion. The alpha-MRE haplotypes and the α-thalassemia mutations spectrum suggest a predominant, but not exclusive, African origin of these mutations in Uruguay.
Highlights
Introduction α-thalassemia is the most common genetic disorder across the world. It is mainly caused by deletions of one (-α) or both (--) HBA genes of the α-globin gene cluster, small deletions or point mutations contribute to the α-thalassemia mutations spectrum (Foglietta et al, 1996; Huisman et al, 1998; Steinberg et al, 2001)
The most common non-deletional alpha thalassemia mutations were analyzed by restriction fragment length polymorphism (RFLP) from products amplified by PCR (Hall et al, 1993)
FST distances between Uruguayan population and other populations were represented in two dimensions by multidimensional scaling (MDS) using the software SPSS 22.0 Data of other populations were obtained from Harteveld et al (2002), Ribeiro et al (2003) and from the 1000 Genomes Database
Summary
A total of 168 unrelated individuals among 1 and 84 years old were analyzed, 117 outpatients from Hospital de Clínicas - Universidad de la República (UdelaR), Montevideo and 51 from Hospital Regional Salto - Administración de Servicios de Salud del Estado (ASSE), recruited in 2015. In adults (≥15 years old) the Hb levels were ≥ 13 g/dL for men and ≥ 12 g/dL for women For both sexes, the VCM and MCH levels were ≤ 80 fl and ≤ 27 pg respectively. For individuals between 12 and 15 years old, we considered Hb levels ≥ 12 and VCM and MCH levels ≤ 78 fl and ≤ 26 pg respectively. All individuals were analyzed for the presence of deletional and non-deletional α-thalassemia mutations. The most common non-deletional alpha thalassemia mutations were analyzed by restriction fragment length polymorphism (RFLP) from products amplified by PCR (αHphα, αNcoIα and ααNcoI) (Hall et al, 1993). HBA1 and HBA2 genes were sequenced to analyzes the presence of point mutations or small deletion (Pedroso et al, 2018; Dodé et al, 1990). Haplotypes were constructed by assuming that the presence of two common haplotypes was more probable than the combination of one common and one rare haplotype or two rare haplotypes (Long et al, 1990; Castro de Guerra et al, 1997)
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