Original investigation

Human Genetics

, Volume 103, Issue 6, pp 639-644

First online:

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

  • J. ReissAffiliated withInstitut für Humangenetik der Universität, Gosslerstrasse 12d, D-37073 Göttingen, Germany e-mail: jreiss@gwdg.de, Fax: +49 551 399 303
  • , Ernst ChristensenAffiliated withUniversity Hospital, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen O, Denmark
  • , Gerhard KurlemannAffiliated withKlinik und Poliklinik für Kinderheilkunde der Universität, Albert-Schweitzer-Strasse 33, D-48149 Münster, Germany
  • , Marie-Therese ZabotAffiliated withHopital Debrousse, Service de Biochimie, F-69322 Lyon Cedex 05, France
  • , Claude DorcheAffiliated withHopital Debrousse, Service de Biochimie, F-69322 Lyon Cedex 05, France

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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.