Mutation update: Variants of the CYB5R3 gene in recessive congenital methemoglobinemia

Abstract

NADH‐cytochrome b5 reductase 3 deficiency is an important genetic cause of recessive congenital methemoglobinemia (RCM) and occurs worldwide in autosomal recessive inheritance. In this Mutation Update, we provide a comprehensive review of all the pathogenic mutations and their molecular pathology in RCM along with the molecular basis of RCM in 21 new patients from the Indian population, including four novel variants: c.103A>C (p.Thr35Pro), c.190C>G (p.Leu64Val), c.310G>T (p.Gly104Cys), and c.352C>T (p.His118Tyr). In this update, over 78 different variants have been described for RCM globally. Molecular modeling of all the variants reported in CYB5R3 justifies association with the varying severity of the disease. The majority of the mutations associated with the severe form with a neurological disorder (RCM Type 2) were associated with the FAD‐binding domain of the protein while the rest were located in another domain of the protein (RCM Type 1).

Recommendations for diagnosis and treatment of methemoglobinemia

“…7 To date, more than 80 different disease-causing variants in the CYB5R3 gene have been reported (HGMD Professional 2020.4), [7][8][9] and genotype-phenotype correlation has been described in this disease. 10,11 Patients with biallelic causative variants in CYB5R3 gene often exhibit erythrocytosis. Based on the severity of the enzyme deficiency, this condition can be classified into two different subtypes:…”

Three novel mutations in CYB5R3 gene causing NADH-cytochrome b5 reductase enzyme deficiency leads to recessive congenital methaemoglobinemia

“…The membrane-bound enzyme is absent in RBCs due to the absence of these organelles [11]. A total of 75 pathogenic variants of CYB5R3 have been reported so far around the globe [12]. Here we describe the molecular basis of type I and type-II methemoglobinemia due to three novel mutations in the CYB5R3 gene causing NADH-CYB5R de ciency in four patients from three distinct regions in India.…”

Neurological and Neuroimaging Features of CYB5R3-Related Recessive Hereditary Methemoglobinemia Type II

“…Recessive hereditary methemoglobinemia (RHM) due to NADH-cytochrome b5 reductase (NADH-CYB5R3) (MIM #250800) deficiency is a rare disease and the most frequent cause of congenital methemoglobinemia. It is caused by mutations in CYB5R3 (MIM #613213), located on chromosome 22q13, for which its alternative splicing generates two isoforms [ 1 ]. The soluble erythrocyte isoform of CYB5R3 is involved in the reduction of methemoglobinemia (MetHb) to hemoglobin, thus restoring the oxygen-binding capacity of hemoglobin.…”

“…In type I (RHM1), the defect is restricted to the erythrocyte soluble form and causes a well-tolerated cyanosis usually with a mild clinical presentation and a normal life expectancy. In type II (RHM2), the deficiency affects both isoforms and impacts red cells and all body tissues, thus resulting in a cyanosis associated with neurological manifestations [ 1 ]. Beyond the previously established concept, according to which neurologic involvement in RHM2 is linked to abnormal lipid metabolism with subsequent neuronal demyelination, recently discovered functions of CYB5R3 in mammalians indicate that other mechanisms, such as synapse depression, vascular nitric oxide insensivity, mitochondrial homeostasis and NAD + depletion, may also play a role [ 2 ].…”