The Mitochondrial Ornithine Carrier 1 (ORC1) protein is encoded by the SLC25A15 (solute carrier family 25, member 15) gene located on chromosome 13q14. ORC1 protein catalyzes the transport of cytosolic ornithine across the inner mitochondrial membrane, from the cytoplasm to the matrix, where it participates in the urea cycle and functions in ammonium detoxification and biosynthesis of the amino acid arginine.
Defects in the ORC1 protein are associated with Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome, an autosomal recessive disorder resulting in various neurologic symptoms, including mental retardation, spastic paraparesis with pyramidal signs, cerebellar ataxia, and episodic disturbance of consciousness or coma caused by hyperammonemia.
The SLC25A15 gene spans a total length of about 35 kb with its six coding exons. The ORC1 protein encoded by this gene consists of 301 amino acids; and weighs about 32.7 kDa. At least 17 mutations in the SLC25A15 gene have been identified in patients with Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome. These mutations cause an alteration in the protein's structure and function, resulting in an unstable protein that lacks the ability to transport ornithine to the mitochondrial matrix. This causes an interruption of the urea cycle and the accumulation of ammonia.
Tessa et al. (2009) identified homozygosity for the p.R179X mutation in affected members of two unrelated families with HHH syndrome from Senegal and Morocco, respectively. In the Moroccan family, one child had onset in infancy of lethargy and coma, and later had liver involvement and coagulopathy, but the other child, who was homozygous for the p.R179X mutation, had no symptoms by age 4 years.
Korman et al. (2004) described two brothers with HHH Syndrome. Sequencing of the SLC25A15 gene identified a homozygous 446G deletion in exon 3 in both patients, which produced a frameshift leading to a premature stop codon in exon 4. Both parents, who were first cousins, were heterozygous for this mutation. In addition, both the affected siblings and their mother were found to be homozygous for a 760A>T SNP in exon 5. This change was also found in additional unrelated controls. The father was heterozygous for this polymorphism.
A novel homozygous mutation in the SLC25A15 gene was identified by Al-Hassnan et al. (2008) in three affected Saudi siblings with HHH syndrome. The mutation was a single base substitution, c.817G>A, resulting in p.Gly220Arg amino acid substitution, which alters the hydropathy status of the protein at this amino acid location. This mutation causes alterations in the protein's structure and function, and it was predicted to be pathogenic.