Haemoglobin Lleida: a new alpha 2-globin variant (12 bp deletion) with mild thalassaemic phenotype

Molecular studies of alpha-thalassaemias have revealed defects at different steps in the process of alpha-gene expression. It is not surprising, therefore, that in some cases a single mutation or small deletion can result in a structurally abnormal haemoglobin that produces the alpha-thalassaemia phenotype. In this report we describe a new unstable alpha-globin variant, Hb Lleida, in a Spanish patient with alpha-thalassaemia trait. The mutation was detected by single-strand conformation polymorphism in the third exon of the alpha 2-globin gene. Direct sequence analysis of the alpha-globin gene showed a 12 bp deletion as the only defect of the alpha 2- and alpha 1-globin genes. The propositus was revealed to be a heterozygous carrier, and two alleles were separated by electrophoresis. This deletion causes the loss of four aminoacid residues (from codon 113 to 116) and would be expected to produce an unstable haemoglobin, as a shorter alpha-globin chain variant is created with 137 amino acids instead of 141 amino acids present in a normal alpha-globin chain. However, no abnormal haemoglobin was found by either isoelectric focusing or haemoglobin electrophoresis. Since the deletion affects an aminoacid residue (114 Pro) involved in alpha 1-beta 1-globin chain contacts, the interaction required for efficient Hb assembly is also compromised. The resulting unstable alpha-globin chain is rapidly catabolized and unsuitable for haemoglobin tetramer formation, causing an alpha-thalassaemia trait phenotype in the heterozygous patient.