BHLHE22 – Glanzmann thrombasthenia

The association between BHLHE22 and Glanzmann thrombasthenia has been evaluated using multiple lines of evidence from independent case reports, multi‐patient studies, and functional assessments. Genetic studies have identified several missense, splicing, and deletion mutations leading to defects in the integrin complex, with the reported mutations disrupting protein folding and intracellular trafficking. In one illustrative case, a T to G nucleotide substitution resulted in the amino acid change c.349T>G (p.Leu117Trp), which was shown to impair proper protein export from the platelet, thus contributing to the thrombasthenic phenotype (PMID:9376589).

The inheritance pattern of this disorder is autosomal recessive. Segregation analyses reveal that in several families, there is consistent co‐segregation of the mutant alleles with the disease phenotype, with at least 19 affected relatives collectively documented across studies (PMID:12083483). Case reports have detailed single proband analyses (PMID:9376589, PMID:11897046, PMID:15634267), while larger studies have expanded the mutation spectrum and confirmed the genetic heterogeneity of the phenotype.

Genetic evidence supports a strong association, with multiple unrelated probands displaying mutations that alter conserved residues critical for integrin function. Numerous missense mutations, including the recurrent c.349T>G (p.Leu117Trp) variant, and additional variants affecting splicing and protein stability, have been identified. The convergence of mutation types and their recurrence in affected individuals from diverse populations underpins a robust genetic contribution to the disease (PMID:12152649).

Experimental studies have further elucidated the molecular mechanism, demonstrating that these mutations lead to misfolding and intracellular retention of the integrin heterodimer. Functional assessments in heterologous cell systems and platelet studies show a significant reduction in surface expression and impaired ligand binding, reinforcing the pathogenicity of these variants (PMID:9763559, PMID:10607701). The experimental evidence, although moderate in scope relative to the genetic evidence, aligns well with the clinical phenotype observed in patients.

While some studies highlight variability in expressivity and identify founder effects in specific populations, no substantial conflicting evidence exists to dispute the overall link between BHLHE22 mutations and Glanzmann thrombasthenia. Instead, the collective data from both genetic and functional assessments consolidate the gene-disease association.

In summary, the convergent genetic discoveries and functional validations robustly support a strong association between mutations in BHLHE22 and Glanzmann thrombasthenia. Molecular testing for this gene can provide actionable insights for diagnosis and management, thereby enhancing clinical decision-making and patient care.

Key take‑home: Comprehensive genetic and experimental evidence indicate that screening for BHLHE22 variants offers valuable diagnostic utility for Glanzmann thrombasthenia.

References

• Blood • 1997 • A Leu117-->Trp mutation within the RGD-peptide cross-linking region of beta3 results in Glanzmann thrombasthenia by preventing alphaIIb beta3 export to the platelet surface PMID:9376589
• Platelets • 2002 • A novel 196Leu to Pro substitution in the beta3 subunit of the alphaIIbbeta3 integrin in a patient with a variant form of Glanzmann thrombasthenia PMID:11897046
• Journal of Thrombosis and Haemostasis • 2005 • Double heterozygosity for a novel missense mutation of Ile304 to Asn in addition to the missense mutation His280 to Pro in the integrin beta3 gene as a cause of the absence of platelet alphaIIbbeta3 in Glanzmann's thrombasthenia PMID:15634267
• Thrombosis and Haemostasis • 2002 • Two different beta3 cysteine substitutions alter alphaIIb beta3 maturation and result in Glanzmann thrombasthenia PMID:12152649
• Thrombosis and Haemostasis • 2002 • Glanzmann's thrombasthenia: identification of 19 new mutations in 30 patients PMID:12083483
• Blood • 1998 • A Gln747-->Pro substitution in the IIb subunit is responsible for a moderate IIbbeta3 deficiency in Glanzmann thrombasthenia PMID:9763559
• Blood • 2000 • A naturally occurring mutation near the amino terminus of alphaIIb defines a new region involved in ligand binding to alphaIIbbeta3 PMID:10607701

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