Novel nonsense mutation in the α1-globin gene [HBA1:C.49A > T] is responsible for non-deletion α-thalassemia

Background: In the alpha-thalassemia one of the less frequent mechanisms is the nonsense mutations, which generate the substitution of a triplet that encodes an amino acid for a stop codon and, therefore, protein synthesis stops prematurely. At present, 9 mutations of this type have been documented, 6 that affect the HBA2 gene and 3 that affect the HBA1 gene. Objectives: We present a new mutation in CD16 of the HBA1 gene, where the change AAG > TAG generates a stop codon. Methods: A 48-year-old woman from Madrid, was studied because she had maintained microcytosis without iron deficiency. Hb A2 and Hb F levels were measured by ion exchange HPLC (VARIANT II). Hemoglobin was studied by capillary zone electrophoresis and ion exchange HPLC (short program of beta-thalassemia). Molecular characterization was performed by automatic sequencing of alpha globin genes. Results: The propositus presented no abnormal hemoglobins and Hb A2 and Hb F levels were within normal limits. The molecular characterization identified the new transversion mutation HBA1: c.49 A > T, which resulted in an amino acid change of Lys > Stop at codon 16 of exon 1 in the state heterozygous [alpha(1)6 (A14) Lys > Stop; HBA1: c.49A > T]. Conclusion: In this new nonsense mutation, short genetic products may suffer nonsense-mediated degradation, whereas the abnormal protein will be eliminated through the proteolytic pathway mediated by ubiquitin. Regardless, the phenotype is mild. The most severe end of the clinical spectrum will probably occur when a mutation is inherited together with a mutation that results in suppression of two genes ( - /alpha alpha(T) or -alpha/ - alpha(T)).