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HBB – Hemoglobin M disease

Congenital methemoglobinemia due to HBB-encoded hemoglobin M variants is characterized by life-long cyanosis and elevated methemoglobin levels. Heterozygous substitutions act via a dominant-negative effect to destabilize the heme environment and accelerate autooxidation to methemoglobin. The beta28(B10)Leu→Met variant (c.85C>A (p.Leu29Met)) was identified in a multi-generation Chilean family with chronic methemoglobinemia and unstable hemoglobin (PMID:10335980). Separately, the beta92(His93)His→Tyr substitution (c.277C>T (p.His93Tyr)) was found in an unrelated patient with congenital methemoglobinemia and Hb E trait (PMID:9494043). Functional assays confirm increased methemoglobin formation consistent with this phenotype ([PMID:10335980]).

References

  • Hemoglobin • 1999 • Hb Chile [beta28(B10)Leu-->Met]: an unstable hemoglobin associated with chronic methemoglobinemia and sulfonamide or methylene blue-induced hemolytic anemia. PMID:10335980
  • Hemoglobin • 1998 • DNA sequence analysis proves Hb M-Milwaukee-2 is due to beta-globin gene codon 92 (CAC-->TAC), the presumed mutation of Hb M-Hyde Park and Hb M-Akita. PMID:9494043

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Two unrelated probands ([PMID:10335980], [PMID:9494043]), segregation in one family (3 affected relatives [PMID:10335980]), concordant functional data

Genetic Evidence

Limited

Two heterozygous HBB variants in separate probands with hemoglobin M disease and minimal segregation

Functional Evidence

Moderate

Functional assays demonstrate unstable hemoglobin variants with increased methemoglobin formation consistent with clinical phenotype