Proteins Structure Models in the Evaluation of Novel Variant (C.472_477del) in the MOCS2 Gene

Abstract

(1) Background: Molybdenum cofactor deficiency type B (MOCODB, #252160) is a rare autosomal recessive metabolic disorder characterized by intractable seizures of neonatal-onset, muscular spasticity, accompanying with hypouricemia, elevated urinary sulfite levels and craniofacial dysmorphism. Thirty-five patients were reported to date. (2) Methods: Our paper aimed to delineate the disease genotype by presenting another patient, in whom a novel, in-frame variant within the MOCS2 gene was identified. (3) Results: Exome sequencing led to the identification of a novel variant in the MOSC2 gene-c.472_477del of unknown significance (VUS). (4) Conclusions: To prove the clinical significance of the mentioned variant, analysis of the possible mutation consequences on molecular level with the use of the available crystal structure of the human molybdopterin synthase complex was of great importance. Moreover, a potential pathomechanism resulting from a molecular defect was presented, giving original insight into the current knowledge on this rare disease, including treatment options.

Ocular characteristics of a 6-year-Old boy with molybdenum cofactor deficiency type B

“…To date, 39 MOCD-B patients with 33 different MOCS2 gene variants have been reported, 4 , 5 , 7 , 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 including this one reported in our study. We reviewed the detail clinical and genetic data of each patient and verified the variants carefully.…”

Live Birth of a Healthy Child in a Couple with Identical mtDNA Carrying a Pathogenic c.471_477delTTTAAAAinsG Variant in the MOCS2 Gene

“…The c.471_477delTTTAAAAinsG variant of the Mocs2 protein has not been reported in the ExAC ( (accessed on 10 March 2023)) or gnomAD ( (accessed on 10 March 2023)) databases. However, the previously described c.472_477del variant [ 5 ] is present in both databases and has a frequency of 1.19 × 10 −5 in gnomAD v.2.1.1 and 1.65 × 10 −5 in ExAC v.1.0. Both of these mutations do not cause a frameshift and result in the same deletion of two amino acids (Leu158 and Lys159) in the protein product (p.Leu158_Lys159del).…”

Molybdenum Cofactor Deficiency in Humans

“…The structure analysis indicated that residues Leu158 and Lys159 are located at the end of the last helix and are involved in the binding of MPT synthase small subunits. Thus, the heterodimer and active complex formation were impaired in this variant [ 68 ]. In conclusion, these studies demonstrate a link between residual Moco synthesis activity and delayed onset and/or a milder course of the disease.…”