Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter.
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: F188delta, 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.
Camacho
J A
JA
Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Obie
C
C
Biery
B
B
Goodman
B K
BK
Hu
C A
CA
Almashanu
S
S
Steel
G
G
Casey
R
R
Lambert
M
M
Mitchell
G A
GA
Valle
D
D
D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D026923:Amino Acid Transport Systems, Basic; D000641:Ammonia / Q000097:blood*; D000818:Animals; D002170:Canada; D002352:Carrier Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13; D002956:Citrulline / Q000378:metabolism*; D005260:Female; D005602:France / Q000208:ethnology; D006580:Genetic Carrier Screening; D006801:Humans; D007621:Karyotyping; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D008969:Molecular Sequence Data; D009492:Neurospora crassa / Q000235:genetics; D009952:Ornithine / Q000097:blood* / Q000378:metabolism; D017354:Point Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics; D016415:Sequence Alignment; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000378:metabolism; D013577:Syndrome; D014162:Transfection
D026923:Amino Acid Transport Systems, Basic; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; C488998:SLC25A2 protein, human; C488997:Slc25a15 protein, mouse; C041356:ornithine transporter; D002956:Citrulline; D000641:Ammonia; D009952:Ornithine