Clinical spectrum and molecular basis of recessive congenital methemoglobinemia in India: Seven novel mutations in the CYB5R3 gene.

Clinical genetics

PubMedID: 24266649

Warang PP, Kedar PS, Shanmukaiah C, Ghosh K, Colah RB. Clinical spectrum and molecular basis of recessive congenital methemoglobinemia in India: Seven novel mutations in the CYB5R3 gene. Clin Genet. 2013;.
We report the clinical features and molecular characterization of 23 patients with cyanosis due to NADH-cytochrome b5 reductase (NADH-CYB5R) deficiency from India. The patients with type I recessive congenital methemoglobinemia (RCM) presented with mild to severe cyanosis only whereas patients with type II RCM had cyanosis associated with severe neurological impairment. Thirteen mutations were identified which included eleven missense mutations causing single amino acid changes [p.Arg49Trp, p.Arg58Gln, p.Pro145Ser, p.Gly155Glu, p.Arg160Pro, p.Met177Ile, p.Met177Val, p.Ile178Thr, p.Ala179Thr, p.Thr238Met, p.Val253Met,] one stop codon mutation (p.Trp236X) and one splice-site mutation (p.Gly76Ser). Seven of these mutations (p.Arg50Trp, p.Gly155Glu, p.Arg160Pro, p.Met177Ile, p.Met177Val, p.Ile178Thr, p.Thr238Met) were novel. Two mutations (p.Gly76Ser, p.Trp236X) were identified for the first time in the homozygous state globally causing type II RCM. We used the three-dimensional (3D) structure of human erythrocyte NADH-CYB5R to evaluate the protein structural context of the affected residues. Our data provides a rationale for the observed enzyme deficiency and contributes to a better understanding of the genotype-phenotype correlation in NADH-CYB5R deficiency.