Observations on the levels of Hb A2 in patients with different beta- thalassemia mutations and a delta chain variant

Abstract

Hb A2 and its variant B2 (alpha 2 delta 2(16)(A13)Gly----Arg) were quantitated in the blood of subjects with three different types of beta- thalassemia and with the delta-B2 anomaly in cis or in trans to the beta-thalassemia determinant. In one family, the delta-B2 mutation was in cis to a newly discovered codon 47 (+A) frameshift. The levels of Hbs A2 and B2 were nearly the same and approximately 70% higher than those in simple Hb B2 heterozygotes. In two additional families, the delta-B2 variant was in trans to either a deletional beta-thalassemia (1,393 bp) involving part of the beta-globin gene and part of the beta- globin gene promoter, or to the -88 C----T promoter mutation. In both instances, the Hb B2 level was increased by approximately 80%, but the Hb A2 level was increased by approximately 270% and 200%, respectively. These data indicate two mechanisms that will cause an increase in delta chain production. One is consistent with a general mechanism concerning the relative excess of alpha chains in beta chain deficiencies which will combine with delta chains to form variable levels of Hb A2 dependent on the severity of the beta chain deficiency. The second concerns the loss of beta-globin gene promoter activity, perhaps by an absence of (or decreased) binding of specific protein(s) to this segment of DNA and a concomitant increase in delta-globin gene promoter activity in cis.

Co‐inheritance of haemoglobin A2′ and beta‐thalassaemia in cis

“…The percentage of HbA2 0 was lower than the percentage of HbA2 in the father and the younger son, as was observed by other authors in patients heterozygous for HbA2 0 and b-thalassaemia minor (Codrington et al, 1990;Van Kirk et al, 2005). Previously reported levels of HbA2 0 on HPLC vary between 1% and 2% in patients with HbA2 0 trait (Joutovsky et al, 2004(Joutovsky et al, , 2005 and between 1% and 2.6% in patients heterozygous for HbA2 0 and b-thalassaemia minor (Codrington et al, 1990;Van Kirk et al, 2005). To define criteria for the diagnosis of HbA2 0 trait by HPLC (Variant II), Van Kirk et al (2005) used a cut-off of <3% for retrospective analysis of 5862 patient samples.…”

“…As the mother had no abnormalities on haemoglobin HPLC, both variants have to be inherited in cis. Co-inheritance of HbA2 0 and b-thalassaemia in cis has been described only once in a family from Suriname which is from mixed African, European and Jewish descent (Huisman, Punt & Schaad, 1961;Codrington et al, 1990). Molecular analysis of the father and his younger son revealed the same mutations as in the family from Suriname, suggesting a possible common origin of both families.…”

“…The mutation in the b gene results in a frameshift and halts synthesis at codon 52 (b 0 -thalassaemia) (Losekoot et al, 1990). This mutation was first described in the family from Suriname with coinheritance in cis of HbA2 0 and beta-thalassaemia (Codrington et al, 1990), suggesting a possible common origin of both families.…”

“…Retrospective analysis in one laboratory revealed that five out of six patients with a suspected b-thalassaemia in combination with HbA2 0 were missed on initial evaluation (Van Kirk, Sandhaus & Hoyer, 2005). Reported levels of HbA2 0 on HPLC vary between 1% and 2% in patients heterozygous for HbA2 0 (Joutovsky et al, 2004(Joutovsky et al, , 2005 and between 1% and 2.6% in patients heterozygous for HbA2 0 and b-thalassaemia minor (Codrington et al, 1990;Van Kirk et al, 2005).…”

HbA2: biology, clinical relevance and a possible target for ameliorating sickle cell disease

“…Mutations in the HBB promoter that favour transcriptional complex interaction with the HBD promoter, alter 3 0 end-processing of the HBB transcript, or affect mRNA splicing account for the transcriptional effect. In the 'mild' b + -thalassaemia mutations, the free a-globin chain pool is decreased, less ad dimer formation occurs, and the HbA 2 is lower than in more 'severe' bthalassaemia mutations (Codrington et al, 1990;Huisman, 1997;Verhovsek et al, 2012). HbA 2 levels in b-thalassaemia trait vary according to the thalassaemia mutation in a relationship that is not always easy to reconcile (Codrington et al, 1990;Huisman, 1997;Verhovsek et al, 2012).…”