AHSP – Beta Thalassemia

This summary evaluates the association between AHSP (HGNC:18075) and beta thalassemia (MONDO_0019402). Multiple well‐designed multi‐patient studies have assessed whether AHSP acts as a genetic modifier in beta thalassemia. In these studies, cohorts of over 120 patients (PMID:14715623) and samples from diverse populations (PMID:16704446, PMID:20627634) failed to reveal any significant association between AHSP haplotypes or variants and disease severity. Consequently, the overall clinical validity of the association is limited by the absence of consistent genotype–phenotype correlations and lack of robust segregation evidence.

From the genetic standpoint, few rare missense variants have been reported – for example, the variant c.224A>T (p.Asn75Ile) identified in a population analysis study (PMID:17874450). However, these variants have not demonstrated consistent segregation with the beta thalassemia phenotype. Thus, the genetic evidence is insufficient to support a direct, causative effect for AHSP in modifying beta thalassemia onset or severity.

In contrast, functional assessments have provided insights into the biological impact of AHSP on hemoglobin assembly. In vitro experiments have shown that impaired binding between AHSP and alpha-globin can lead to unstable hemoglobins, as noted in studies evaluating the interaction defects associated with certain alpha chain variants (PMID:17052927). Additionally, mutagenesis studies have demonstrated that alterations in AHSP can change its binding kinetics and stability properties (PMID:22287545), suggesting a plausible mechanistic impact that is, however, not reflected clinically.

Overall, despite robust experimental evidence highlighting a potential mechanism whereby AHSP influences alpha-globin stability, the clinical genetic evidence fails to establish a significant association with beta thalassemia. This discordance underscores the complex nature of thalassemic phenotypes which may be influenced by multiple genetic and environmental factors.

The current evidence suggests that while AHSP may modulate aspects of hemoglobin biochemistry, its utility as a clinical diagnostic marker or therapeutic target for beta thalassemia is limited. Further large-scale, multi-population studies would be required to clarify any subtle genetic modifiers that could complement existing diagnostic decision-making.

Key Take‑home: Although in vitro data indicate that defective AHSP can disrupt hemoglobin stability, the lack of consistent genetic association limits its immediate clinical utility in beta thalassemia.

References

• Blood • 2004 • Evaluation of alpha hemoglobin stabilizing protein (AHSP) as a genetic modifier in patients with beta thalassemia PMID:14715623
• British journal of haematology • 2006 • Alpha-haemoglobin stabilising protein is a quantitative trait gene that modifies the phenotype of beta-thalassaemia PMID:16704446
• Blood cells, molecules & diseases • 2010 • Analysis of alpha-hemoglobin-stabilizing protein (AHSP) gene as a genetic modifier to the phenotype of beta-thalassemia in Southern China PMID:20627634
• Blood cells, molecules & diseases • 2006 • Impaired binding of AHSP to alpha chain variants: Hb Groene Hart illustrates a mechanism leading to unstable hemoglobins with alpha thalassemic like syndrome PMID:17052927
• American journal of hematology • 2008 • Population analysis of the alpha hemoglobin stabilizing protein (AHSP) gene identifies sequence variants that alter expression and function PMID:17874450
• The Journal of biological chemistry • 2012 • Insights into hemoglobin assembly through in vivo mutagenesis of α-hemoglobin stabilizing protein PMID:22287545

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