CYB5R3 – Methemoglobinemia Due to Methemoglobin Reductase Deficiency

Congenital methemoglobinemia due to CYB5R3 deficiency is an autosomal recessive disorder presenting as type I (erythrocyte-restricted enzyme deficiency with benign cyanosis) or type II (generalized deficiency with severe neurological impairment) (PMID:21349748).

Genetic evidence includes over 30 unrelated probands from diverse ethnic backgrounds (Indian, Mexican, Greek, African-American, Thai, Chinese, UK) with biallelic CYB5R3 variants, confirming AR inheritance and diagnostic yield across populations (PMID:21349748; PMID:2107882).

The variant spectrum comprises >78 pathogenic alleles, including missense (e.g., c.470T>G (p.Phe157Cys)), nonsense (e.g., c.250C>T (p.Arg84Ter)), splice-site (e.g., c.547+1G>A), small deletions (e.g., c.817_819del (p.Met273del)), and frameshifts, with recurrent founder alleles such as p.Arg192Cys in Indian families (PMID:29482478; PMID:31898843).

Segregation analyses in multiple sibships demonstrate concordant homozygosity or compound heterozygosity in affected relatives (e.g., two affected siblings for c.382T>C (p.Ser128Pro)) and obligate carrier parents (PMID:2107882).

Functional assays of recombinant mutant CYB5R3 proteins reveal markedly reduced enzymatic activity (<10% of wild type), decreased thermal stability, altered kinetic parameters, and increased protease susceptibility, consistent with a loss-of-function mechanism (PMID:21349748).

Integrating genetic and biochemical data confirms CYB5R3 deficiency as a definitive cause of recessive methemoglobinemia. Accurate molecular diagnosis enables genotype-phenotype correlations (type I vs. II), informs carrier screening, and supports prenatal testing. Key take-home: CYB5R3 mutation analysis is essential for definitive diagnosis and management of congenital methemoglobinemia.

References

• Blood cells, molecules & diseases • 2011 • Molecular basis of two novel mutations found in type I methemoglobinemia. PMID:21349748
• Blood • 1990 • Serine-proline replacement at residue 127 of NADH-cytochrome b5 reductase causes hereditary methemoglobinemia, generalized type. PMID:2107882
• Hematology (Amsterdam, Netherlands) • 2018 • Novel mutation (R192C) in CYB5R3 gene causing NADH-cytochrome b5 reductase deficiency in eight Indian patients associated with autosomal recessive congenital methemoglobinemia type-I. PMID:29482478
• Human mutation • 2020 • Mutation update: Variants of the CYB5R3 gene in recessive congenital methemoglobinemia. PMID:31898843

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