Genomic structure and mutational spectrum of the bicistronic MOCS1 gene defective in molybdenum cofactor deficiency type A

Abstract

Molybdenum cofactor (MoCo) deficiency is a rare and devastating disease resulting in neonatal seizures and other neurological symptoms identical to those of sulphite oxidase deficiency. It is an autosomal recessive disease and no therapy is known. Most patients harbour MOCS1 mutations, which are found in both open reading frames of this unusual gene encoding the first two enzymes required in the MoCo biosynthesis pathway, MOCS1 A and MOCS1 B, in a single transcript. We describe genomic details as a prerequisite for comprehensive mutation analysis. In an initial cohort of 24 MoCo deficiency patients, we identified 13 different mutations on 34 chromosomes, with a mutation detection rate of 70%. Five mutations were observed in more than one patient and together accounted for two thirds of detected mutations. These comprise the most frequent mutation, R319Q, which is restricted to England, two Danish/German mutations (one missense and one splice site mutation), a missense mutation found in England and Germany, and a "Mediterranean" frameshift mutation. All patients with identified mutations are either homozygous or compound heterozygous for mutations in either of the two open reading frames corresponding to MOCS1 A and MOCS1 B, respectively. This observation suggests the existence of more than the two previously described complementation groups in MoCo biosynthesis.

Molybdenum cofactor deficiency: first prenatal genetic analysis

“…The MoCo deficiency locus on chromosome 6 has been shown to be responsible for the majority of cases (Reiss et al, 1998b) and thus, in principle, often will be linked to the disease and useful in segregation analysis. However, consanguinity is not rare in families with MoCo deficient patients, which might complicate the identification of informative markers in indirect genotyping.…”

“…DNA was isolated from cultured chorionic cells. Amplification and sequencing of the MOCS1 gene exon 2 was done as described by Reiss et al (1998b). PCR products were column-purified (Qiagen) and directly sequenced in cycles according to the dye-terminator protocol with subsequent analysis on a 370A automated sequencer (ABI).…”

“…Most patients with molybdenum cofactor (MoCo) deficiency (reviewed in Johnson and Wadman, 1995) harbour MOCS1 mutations and the splice site mutation 418+1G<A was identified in two Danish and one German families (Reiss et al, 1998b). Prenatal diagnosis was now requested by a Danish family with two patients homozygous for the 418+1G<A mutation which leads to the omission of exon 2 of the MOCS1 gene transcript and consequently to a complete loss of all molybdo-enzyme activities (Reiss et al, 1998b;Krawczak et al, 1992;Menendez et al, 1996).…”

The neurotransmitter receptor-anchoring protein gephyrin reconstitutes molybdenum cofactor biosynthesis in bacteria, plants, and mammalian cells

“…However, the recently described mocs1 gene (9) has been shown to be responsible for the majority of cases (42), and most of the remaining cases can be attributed to mutations in mocs2 encoding molybdopterin synthase (unpublished observations). Whether a few patients bear mutations in mocs3 (GenBank accession no.…”

Shared function and moonlighting proteins in molybdenum cofactor biosynthesis

“…In humans, the MOCS1 locus encodes two proteins, MOCS1A and MOCS1B, which are homologous to the bacterial MoaA and MoaC proteins, respectively (Reiss et al, 1998a). An unusual bicistronic transcript of the MOCS1 locus was identified, with open reading frames for both MOCS1A and MOCS1B in a single transcript, separated by a stop codon (Reiss et al, 1998b;Gross-Hard and Reiss, 2002).…”