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

Molybdenum cofactor (MoCo) deficiency is a rare and devastating disease res ulting in neonatal seizures and other neurological symptoms identical to th ose of sulphite oxidase deficiency. It is an autosomal recessive disease an d no therapy is known. Most patients harbour MOCSI mutations, which are fou nd in both open reading frames of this unusual gene encoding the first two enzymes required in the MoCo biosynthesis pathway, MOCS I A and MOCS 1 B, i n a single transcript. We describe genomic details as a prerequisite for co mprehensive mutation analysis. In an initial cohort of 24 MoCo deficiency p atients, we identified 13 different mutations on 34 chromosomes, with a mut ation 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" fram eshift mutation. All patients with identified mutations are either homozygo us or compound heterozygous for mutations in either of the two open reading frames corresponding to MOCS1 A and MOCS 1 B, respectively. This observati on suggests the existence of more than the two previously described complem entation groups in MoCo biosynthesis.