Novel Compound Heterogeneous Mutations in <i>CYB5R3</i> Gene Leading to Methemoglobinemia (Type I) in a Chinese Boy: Case Report and Relevant Comprehensive Analysis

Abstract

<b><i>Introduction:</i></b> Recessive congenital methemoglobinemia (RCM) caused by CYB5R3 deficiency due to the mutations in the reduced nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (<i>CYB5R</i>) gene is an autosomal recessive inherited disease. Clinically, it can be divided into two types, namely red blood cell affected type (RCM I) and systemically affected type (RCM II). <b><i>Case Presentation:</i></b> A 5-year-old male patient was diagnosed with cyanosis for 5 years. Physical examination showed cyanosis in areas such as the lips, fingers, and toes. Laboratory examination revealed low pulse oxygen saturation (81%) and increased blood methemoglobin (23.6%). Gene testing revealed the compound heterozygous mutations in the <i>CYB5R3</i> gene, c.149G&gt;A (p.Arg50Gln) and c.331A&gt;G (p.Lys111Glu), respectively originating from his parents. By constructing 3D models of <i>CYB5R3</i> wild-type and mutant types using SWISS-MODEL software, it was found that the mutation caused significant structural abnormalities in the CYB5R protein. The relationship between <i>CYB5R3</i> gene mutation sites, amino acid change, enzyme activity, and methemoglobinemia type I and II were listed and analyzed. <b><i>Conclusion:</i></b> A case of congenital RCM type I caused by compound heterozygous mutations in the <i>CYB5R3</i> gene was reported, with c.331A&gt;G (p.Lys111Glu) being the newly reported mutation. The homozygosity or heterozygosity of <i>CYB5R3</i> gene mutations that lead to premature termination, loss of exons, and change in amino acid properties in FAD or NADH binding domains, is positively correlated with the severity (from type I to type II) of methemoglobinemia.