Evaluation of alpha hemoglobin stabilizing protein (AHSP) as a genetic modifier in patients with β thalassemia

Abstract

Although ␤ thalassemia is considered to be a classic monogenic disease, it is clear that there is considerable clinical variability between patients who inherit identical ␤ globin gene mutations, suggesting that there may be a variety of genetic determinants influencing different clinical phenotypes. It has been suggested that variations in the structure or amounts of a highly expressed red cell protein (alpha hemoglobin stabilizing protein [AHSP]), which can stabilize free ␣ globin chains in vitro, could influence disease severity in patients with ␤ thalassemia. To address this hypothesis, we studied 120 patients with Hb E-␤ thalassemia with mild, moderate, or severe clinical phenotypes. Using gene mapping, direct genomic sequencing, and extended haplotype analysis, we found no mutation or specific association between haplotypes of AHSP and disease severity in these patients, suggesting that AHSP is not a disease modifier in Hb E-␤ thalassemia. It remains to be seen if any association between AHSP and clinical severity is present in other population groups with a high frequency of ␤ thalassemia.

The Role of Alpha-Hemoglobin Stabilizing Protein in Redox Chemistry, Denaturation, and Hemoglobin Assembly

“…The relationships between AHSP and the thalassemia syndromes have been examined recently because these disorders involve HbA biosynthesis and a H and b H chain instability. Viprakasit et al (105) investigated whether variations in the apparent clinical severity of Hb E b thalassemia could be explained by the presence of mutant Ahsp alleles among affected individuals. Several single nucleotide polymorphisms (SNPs) were identified, but none of them were found to correlate with the severity of the thalassemic phenotype (105).…”

“…Viprakasit et al (105) investigated whether variations in the apparent clinical severity of Hb E b thalassemia could be explained by the presence of mutant Ahsp alleles among affected individuals. Several single nucleotide polymorphisms (SNPs) were identified, but none of them were found to correlate with the severity of the thalassemic phenotype (105). Other work has shown that both healthy and thalassemic individuals may possess an uncommon missense mutation that results in AHSP with an isoleucine at position 75 instead of an asparagine (N75I) (28).…”

A Twins Heritability Study on Alpha Hemoglobin Stabilizing Protein (AHSP) Expression Variability

“…Previously we reported that a certain AHSP haplotype has a lower level of expression and was related to a more severe phenotype of β-thalassemia (Lai et al, 2006). The allelic frequency of this AHSP haplotype was also found to be higher in a group of Hb E/ β-thalassemia patients compared to their non-thalassemic control group in Thailand by Viprakasit et al, 2004. However, when they analyzed this patient group with a non-thalassemic control group from another province, the AHSP allele frequency and haplotypes were more similar (Viprakasit et al, 2004).…”

Controlling -globin: a review of -globin expression and its impact on -thalassemia

“…48,50 These studies in mice indicate that AHSP may be a possible modifier gene in human β-thalassemias. However, mutations which ablate AHSP in humans are rare 49,54 and investigations into possible effects of reduced AHSP expression in β-thalassemia have so far been largely inconclusive. Preliminary reports indicate that AHSP may be a modifier in the human population 48,[55][56][57] but as yet, there has been little definitive evidence that this is the case.…”