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

Abstract

Two types of recessive congenital methaemoglobinemia (RCM) is caused by NADH-dependent cytochrome b5 reductase enzyme de ciency encoded by CYB5R3 gene. RCM-I is characterized by higher methaemoglobin levels (>2 g/dL), causing only cyanosis, whereas RCMR-II is associated with cyanosis with neurological impairment. The present study discovered three novel homozygous pathogenic variants of CYB5R3 causing RCM I and II in four unrelated Indian patients. In patient-1 and patient-2 of are of RCM type I caused due to novel c.175C>T (p.Arg59Cys) and other reported c.469T>C (p.Phe157Ser) missense pathogenic variants respectively, whereas patient-3 and patient-4 presented with the RCM type II are related to developmental delay with cyanosis since birth due to a novel homozygous (g.25679_25679delA) splice-site deletion and novel homozygous c.824_825insC (p.Pro278ThrfsTer367) single nucleotide insertion. The CYB5R3 transcript levels were estimated by qRT-PCR in the splice-site deletion, which was 0.33fold of normal healthy control. The insertion of nucleotide C resulted in a frameshift of termination codon are associated with neurological impairment. This study can help to conduct genetic counselling and, subsequently, prenatal diagnosis of high-risk genetic disorders.

Methemoglobinemia, Increased Deformability and Reduced Membrane Stability of Red Blood Cells in a Cat with a CYB5R3 Splice Defect

“…More than 80 CYB5R3 variants have been reported in human patients with RCM [ 5 , 7 , 12 , 13 ], but a comparable splice defect, as described herein, has not yet been reported in human patients. Humans with type I RCM commonly have missense CYB5R3 variants in exon 2–9, while those with type II frequently have CYB5R3 variants leading to protein truncations [ 7 ].…”

“…In contrast, human patients with membrane-bound CYB5R3 deficiency, referred to as type II RCM, exhibit developmental abnormalities and neurologic impairments (Type II RCM: OMIM #250800) [ 10 , 11 ]. More than 80 different pathogenic variants in the CYB5R3 gene and their correlation with either type I or type II RCM have been reported in human patients [ 5 , 7 , 12 , 13 ].…”

Molecular Dynamic Simulation Analysis of a Novel Missense Variant in CYB5R3 Gene in Patients with Methemoglobinemia

“…The most common methemoglobinemia is type 1 which includes a tolerable form marked by a highly documented clinical representation of cyanosis. Methemoglobinemia type II (generalized) affects all tissues of the body and manifests in cyanosis as well as neurological complications [ 9 , 10 ]. Recently, congenital methemoglobinemia was also reported in a patient with multiple limb anomalies [ 11 ].…”