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Hyperornithinaemia- hyperammonaemia- homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter

Nature Genetics volume 22, pages 151–158 (1999)Cite this article

Abstract

Neurospora crassa ARG13 and Saccharomyces cerevisiae ARG11 encode mitochondrial carrier family (MCF) proteins that transport ornithine across the mitochondrial inner membrane. We used their sequences to identify EST candidates that partially encode orthologous mammalian transporters. We thereby identified such a gene (ORNT1) that maps to 13q14 and whose expression, similar to that of other urea cycle (UC) components, was high in liver and varied with changes in dietary protein. ORNT1 expression restores ornithine metabolism in fibroblasts from patients with hyperammonaemia-hyperornithinaemia -homocitrullinuria (HHH) syndrome. In a survey of 11 HHH probands, we identified 3 ORNT1 mutant alleles that account for 21 of 22 possible mutant ORNT1 genes in our patients: F188Δ, which is common in French-Canadian HHH patients and encodes an unstable protein; E180K, which encodes a stable, properly targeted protein that is inactive; and a 13q14 microdeletion. Our results show that ORNT1 encodes the mitochondrial ornithine transporter involved in UC function and is defective in HHH syndrome.

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Figure 1: Expression of a candidate gene encoding a mammalian ornithine transporter.
Figure 2: Sequence alignment of human (Hs), mouse (Mm), N. crassa (Nc) and S. cerevisiae (Sc) MCF ornithine transporters.
Figure 3: ORNT1 expression restores incorporation of ornithine radiolabel into cellular protein in HHH fibroblasts.
Figure 4: ORNT1 mutations in HHH.
Figure 5: Survey of HHH probands and French-Canadian controls for F188Δ.
Figure 6: Two-colour FISH analysis of a metaphase chromosome spread from HHH011.
Figure 7: Expression of ORNT1 mutant alleles.
Figure 8: Subcellular location of wild-type and mutant ORNT1 transporters.

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Acknowledgements

We thank B. Soares for supplying EST AH007255, J. Proffitt and Vysis, Inc. for providing the 13qtel probe and S. Muscelli for assistance in preparing the manuscript. J.A.C. is supported by an NIGMS Postdoctoral Training Grant (GM07471). Part of this work was supported by a grant from the National Eye Institute (EY07414) to D.V. and NICHD Mental Retardation Research Center Core Grant (HD24061) to B.K.G.

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Authors and Affiliations

  1. Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Jose A. Camacho, Chien-An Hu & David Valle

  2. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Cassandra Obie, Barbara Biery, Shlomo Almashanu, Gary Steel & David Valle

  3. Department of Gynecology and Obstetrics and the Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Barbara K. Goodman

  4. Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada

    Robin Casey

  5. Department of Pediatrics, Hôpital Ste-Justine, Montreal, Canada

    Marie Lambert & Grant A. Mitchell

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Camacho, J., Obie, C., Biery, B. et al. Hyperornithinaemia- hyperammonaemia- homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet 22, 151–158 (1999). https://doi.org/10.1038/9658

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