Molybdopterin synthase mutations in a mild case of molybdenum cofactor deficiency

Abstract

Molybdenum cofactor deficiency is a rare inborn error of metabolism with generally severe symptoms, most often including neonatal seizures and severe developmental delay. We describe a patient with an unusually mild form of the disease. Two mutations in MOCS2A (molybdenum cofactor synthesis enzyme 2A) were identified: a single base change, 16C > T, that predicts a Q6X substitution on one allele and a 19G > T transversion that predicts a valine to phenylalanine substitution, V7F, on the second. It is postulated that the milder clinical symptoms result from a low level of residual molybdopterin synthase activity derived from the 19G > T allele.

Mechanistic Studies of Human Molybdopterin Synthase Reaction and Characterization of Mutants Identified in Group B Patients of Molybdenum Cofactor Deficiency

“…Only a few group B patients have been identified to date, and they are generally very severely affected by the disease (2). However, one patient identified with an unusually mild form of the disease, harbored a valine to phenylalanine exchange at the N terminus of MOCS2A (19), and it was speculated that a low level of residual activity from the V7F allele might be responsible for the milder clinical symptoms (19). CD spectroscopy of the purified MOCS2A-V7F variant showed that the mutation altered the protein structure sufficiently to produce noticeable differences in both its ␤-strand and ␣-helical composition.…”

“…The moaD gene lacks 15 of the first 18 bases present in MOCS2A, and the MoaD protein has an isoleucine at position 2 corresponding to Val 7 in MOCS2A. Introducing the bulkier phenylalanine at position 2 instead of valine would disrupt the structure at the N terminus of the small subunit, indirectly affecting enzyme activity (19). Our analyses support and extend this statement by documenting that the structure of MOCS2A-V7F is altered in a manner that disturbs its interaction with MOCS2B and results in accumulation of a one-sulfur intermediate (13).…”

“…Among these patients, the majority are in group A and only a few of the mutations identified in the patients have been located in the genes for either MOCS2A or MOCS2B (2). It has been reported that most group B patients are very severely affected (2); however, one patient identified with an unusually mild form of the disease was heterozygous for two single-base substitutions in MOCS2A (19). The mutation in one allele introduced a stop codon in place of a glutamine (Q6X), and the mutation in the second allele resulted in substitution of a valine for a phenylalanine (V7F).…”

“…The mutation in one allele introduced a stop codon in place of a glutamine (Q6X), and the mutation in the second allele resulted in substitution of a valine for a phenylalanine (V7F). It was speculated that a low level of residual activity from the V7F allele might be responsible for the milder clinical symptoms of this patient (19). To analyze the molecular basis of base pair exchanges leading to molybdenum cofactor deficiency in group B patients, these mutations were introduced in either MOCS2A or MOCS2B by site-directed mutagenesis.…”

“…A number of mutations in the MOCS2 proteins have been identified in group B patients. Whereas one patient described with an amino acid exchange in MOCS2A showed a particularly mild form of molybdenum cofactor deficiency, two patients with mutations identified in MOCS2B were severely affected (19). To analyze differences in symptoms of Moco deficiency based on varying MPT synthase activities, corresponding mutants in MOCS2A and MOCS2B have been generated and characterized.…”