CYB5R3 – Hereditary Methemoglobinemia

Hereditary methemoglobinemia is an autosomal recessive disorder caused by NADH-cytochrome b5 reductase (CYB5R3) deficiency, characterized by impaired electron transfer to cytochrome b5 and chronic cyanosis with or without neurological impairment ([PMID:2107882]). The erythrocyte‐restricted form (type I) presents with lifelong cyanosis (HP:0000960), whereas the generalized form (type II) includes severe neurological features such as microcephaly (HP:0000252) and seizures (HP:0001250) ([PMID:11215870]).

Genetic evidence comprises five unrelated probands with homozygous or compound heterozygous CYB5R3 variants ([PMID:2107882], [PMID:11215870], [PMID:11295830], [PMID:28649542], [PMID:35064402]). In one family, the c.382T>C (p.Ser128Pro) variant segregated with disease in two affected siblings and a heterozygous parent, confirming autosomal recessive inheritance ([PMID:2107882]).

The variant spectrum includes missense changes (c.382T>C (p.Ser128Pro), c.535G>A (p.Ala179Thr), c.757G>A (p.Val253Met), p.K173_p.V175del3), splice‐site mutations (IVS4−2A>G), and nonsense alleles (c.82C>T (p.Gln28Ter)), collectively disrupting FAD‐ or NADH‐binding domains and reducing protein stability.

Functional assays demonstrate that patient‐derived lymphoblasts retain ≤10% of normal CYB5R3 activity despite normal transcript and protein levels, indicating conformational loss of function ([PMID:2107882]). Recombinant expression of missense mutants reveals decreased thermostability, altered spectral properties, and complete absence of detectable enzyme for splice‐site variants ([PMID:8874222], [PMID:11295830]). Molecular modeling corroborates that in‐frame deletions abrogate core stability ([PMID:28649542]).

No studies refute the association. The concordance of multiple proband reports, familial segregation, and consistent functional impairment establishes a strong gene–disease relationship. CYB5R3 loss‐of‐function underlies both type I and II methemoglobinemia.

Key take-home: CYB5R3 pathogenic variants cause autosomal recessive methemoglobinemia via loss‐of‐function mechanisms, enabling definitive molecular diagnosis and informed genetic counselling.

References

• Blood • 1990 • Serine-proline replacement at residue 127 of NADH-cytochrome b5 reductase causes hereditary methemoglobinemia, generalized type. PMID:2107882
• Journal of the Medical Association of Thailand • 2000 • A Thai boy with hereditary enzymopenic methemoglobinemia type II. PMID:11215870
• Human Mutation • 2001 • Molecular basis of recessive congenital methemoglobinemia, types I and II: Exon skipping and three novel missense mutations in the NADH-cytochrome b5 reductase (diaphorase 1) gene. PMID:11295830
• Blood • 1996 • Two novel mutations in the reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase gene of a patient with generalized type, hereditary methemoglobinemia. PMID:8874222
• Molecular genetics and metabolism reports • 2015 • A novel nine base deletion mutation in NADH-cytochrome b5 reductase gene in an Indian family with recessive congenital methemoglobinemia-type-II. PMID:28649542
• Molecular biology reports • 2022 • Three novel mutations in CYB5R3 gene causing NADH-cytochrome b5 reductase enzyme deficiency leads to recessive congenital methaemoglobinemia. PMID:35064402

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