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

Neurospora crassa ARG13 and Saccharomyces cerevisiae ARG11 I en code mitoch ondrial carrier family (MCF) proteins that transport ornithine across the m itochondrial inner membrane,. We used their sequences to identify EST candi dates that partially encode orthologous mammalian transporters. We thereby identified such a gene (ORNT1) that maps to 13q14 and whose expression, sim ilar to that of other urea cycle (UC) components, was high in liver and var ied with changes in dietary protein. ORNT1 expression, restores ornithine m etabolism in fibroblasts from patients with hyperammonaemia-hyperornithinae mia-homocitrullinuria (HHH) syndrome. In a survey of 11 HHH probands, we id entified 3 ORNT1 mutant alleles that account for 21 of 22 possible mutant O RNT1 genes in our patients: F188 Delta which is common in French-Canadian H HH 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 in volved in UC function and is defective in HHH syndrome.