α-thalassaemia due to a single codon deletion in the α-1-globin gene. Computational structural analysis of the new α-chain variant

✍ Scribed by Sonia Ayala; Dolors Colomer; Josep Lluís Gelpí; Joan Lluís Vives Corrons

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 146 KB
• Volume: 11
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/(sici)1098-1004(1998)11:5<412::aid-humu14>3.0.co;2-r

✦ Synopsis

A new unstable -globin chain associated with -thalassemia phenotype has been found in a Spanish patient. Molecular analysis of the -globin gene complex using PCR and non-radioactive single-strand conformation analysis, allowed to identify a new mutation in the second exon of the 1 -globin gene. Direct sequencing of the abnormal fragment revealed a 3 bp deletion, which led to the loss of a single codon corresponding to a Lys (K) residue at position 60 or 61 ( K60 or K61). Theoretical structural analysis, performed by computational methods, indicated that the loss of an amino acid residue at this position disturbed the contact region between the B and E-helices, affecting the overall stability of the molecule. Therefore, the K60 or K61 results in a structurally abnormal -globin chain, not previously described, named Hb Clinic, which leads to the -thalassemia phenotype in the heterozygote patient. No abnormal hemoglobin was detected by standard electrophoretic procedures, suggesting that this -globin chain variant is so unstable that it may be catabolized immediately after its synthesis. This mutation was confirmed by PCR using an allele specific primer.