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Mutations in a polycistronic nuclear gene associated with molybdenum cofactor deficiency

Nature Genetics volume 20, pages 51–53 (1998)Cite this article

Abstract

All molybdoenzymes other than nitrogenase require molybdopterin as a metal-binding cofactor1. Several genes necessary for the synthesis of the molybdenum cofactor (MoCo) have been characterized in bacteria2,3 and plants4. The proteins encoded by the Escherichia coli genes moaA and moaC catalyse the first steps in MoCo synthesis. The human homologues of these genes are therefore candidate genes for molybdenum cofactor deficiency, a rare and fatal disease5. Using oligonucleotides complementary to a conserved region in the moaA gene, we have isolated a human cDNA derived from liver mRNA. This transcript contains an open reading frame (ORF) encoding the human moaA homologue and a second ORF encoding a human moaC homologue. Mutations can be found in the majority of MoCo-deficient patients that confirm the functional role of both ORFs in the corresponding gene MOCS1 (for `molybdenum cofactor synthesis-step 1'). Northern-blot analysis detected only full-length transcripts containing both consecutive ORFs in various human tissues. The mRNA structure suggests a translation reinitiation mechanism for the second ORF. These data indicate the existence of a eukaryotic mRNA, which as a single and uniform transcript guides the synthesis of two different enzymatic polypeptides with disease-causing potential.

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Figure 1: Nucleotide sequence and deduced amino acid sequence of MOCS1 in the transition region between ORF A and ORF B.
Figure 2: Alignment of the proteins MOCS1A, CNX2 and MOAA (a) and of MOCS1B, CNX3 and MOAC (b), respectively.
Figure 3: Northern-blot analysis of various human tissues with a MOCS1 probe.
Figure 4: Pedigrees and sequence analysis of the two families described in the text.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (Re768/5-1,2). The authors thank S. Haurand and U. Lenz for their excellent assistance, many `cytos' for their hospitality and technical help, B. Lemcke, B. Wittwer and B. Zöller for DNA samples, P. Burfeind, W. Engel, A. Gal, M. Horst and J. Kohlhase for helpful discussions and G. Schlüter for critical reading of the manuscript.

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Authors and Affiliations

  1. Institut für Humangenetik, Gosslerstrasse 12d, Göttingen, D-37073, Germany

    Jochen Reiss

  2. Abteilung Biochemie II der Universität, Gosslerstrasse 12d, Göttingen, D-37073, Germany

    Thomas Dierks

  3. Department of Genetics, Tamkin Human Molecular Genetics Research Facility, Technion-Israel Institute of Technology, P.O.B. 9649, Bat-Galim, Haifa, 31096, Israel

    Nadine Cohen

  4. Department of Pediatrics, Rambam Medical Center, Technion-Israel Institute of Technology, P.O.B. 9649, Bat-Galim, Haifa, 31096, Israel

    Hanna Mandel

  5. Hopital Debrousse, Service de Biochimie, Cedex 05, Lyon, 69322, France

    Claude Dorche & Marie-Therese Zabot

  6. Botanisches Institut der Technischen Universität , Humboldtstrasse 1, Braunschweig , D-38106, Germany

    Ralf R. Mendel & Birgit Stallmeyer

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Correspondence to Jochen Reiss.

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Reiss, J., Cohen, N., Dorche, C. et al. Mutations in a polycistronic nuclear gene associated with molybdenum cofactor deficiency. Nat Genet 20, 51–53 (1998). https://doi.org/10.1038/1706

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