RGD Reference Report - Molecular basis of two novel mutations found in type I methemoglobinemia. - Rat Genome Database

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Molecular basis of two novel mutations found in type I methemoglobinemia.

Authors: Lorenzo FR, 5TH  Phillips, JD  Nussenzveig, R  Lingam, B  Koul, PA  Schrier, SL  Prchal, JT 
Citation: Lorenzo FR 5th, etal., Blood Cells Mol Dis. 2011 Apr 15;46(4):277-81. doi: 10.1016/j.bcmd.2011.01.005. Epub 2011 Feb 24.
RGD ID: 11040533
Pubmed: PMID:21349748   (View Abstract at PubMed)
PMCID: PMC3075332   (View Article at PubMed Central)
DOI: DOI:10.1016/j.bcmd.2011.01.005   (Journal Full-text)

Congenital methemoglobinemia due to NADH-cytochrome b5 reductase 3 (CYB5R3) deficiency is an autosomal recessive disorder that occurs sporadically worldwide, although endemic clusters of this disorder have been identified in certain ethnic groups. It is present as two distinct phenotypes, type I and type II. Type I methemoglobinemia is characterized by CYB5R3 enzyme deficiency restricted to erythrocytes and is associated with benign cyanosis. The less frequent type II methemoglobinemia is associated with generalized CYB5R3 deficiency affecting all cells and is lethal in early infancy. Here we describe the molecular basis of type I methemoglobinemia due to CYB5R3 deficiency in four patients from three distinct ethnic backgrounds, Asian Indian, Mexican and Greek. The CYB5R3 gene of three probands with type I methemoglobinemia and their relatives were sequenced revealing several putative causative mutations; in one subject multiple mutations were present. Two novel mutations, S54R and F157C, were identified and the previously described A179T, V253M mutations were also identified. All these point mutations mapped to the NADH binding domain and or the FAD binding domain. Each has the potential to sterically hinder cofactor binding causing instability of the CYB5R3 protein. Wild-type CYB5R3, as well as two of these novel mutations, S54R and F157C, was amplified, cloned, and purified recombinant peptide obtained. Kinetic and thermodynamic studies of these proteins show that the above mutations lead to decreased thermal stability.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
NADH Cytochrome B5 Reductase Deficiency  IAGP 11040533DNA:mutations:exons and 3'UTR:RGD 
NADH Cytochrome B5 Reductase Deficiency  ISOCYB5R3 (Homo sapiens)11040533; 11040533DNA:mutations:exons and 3'UTR:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyb5r3  (cytochrome b5 reductase 3)

Genes (Mus musculus)
Cyb5r3  (cytochrome b5 reductase 3)

Genes (Homo sapiens)
CYB5R3  (cytochrome b5 reductase 3)


Additional Information