Alternative titles; symbols
HGNC Approved Gene Symbol: SLC25A15
SNOMEDCT: 30287008; ICD10CM: E72.4;
Cytogenetic location: 13q14.11 Genomic coordinates (GRCh38) : 13:40,789,611-40,812,460 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q14.11 | Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome | 238970 | Autosomal recessive | 3 |
The SLC25A15 gene encodes the mitochondrial ornithine transporter, which transports ornithine across the inner mitochondrial membrane from the cytosol to the mitochondrial matrix. This is a vital step in the urea cycle, which serves to eliminate toxic ammonium ions from the breakdown of nitrogen (summary by Camacho et al., 1999).
The fungi Neurospora crassa Arg13 and Saccharomyces cerevisiae Arg11 genes encode mitochondrial carrier family proteins that transport ornithine across the mitochondrial inner membrane. Camacho et al. (1999) used these sequences to identify a human expressed sequence tag (EST) corresponding to the orthologous human transporter. The SLC25A15 gene, which they termed ORNT1, encodes a 301-residue protein with 95% identity to mouse Ornt1 and 28% identity to Neurospora Arg13. The protein has 3 repeats of about 100 amino acids and each repeat has 2 predicted transmembrane alpha-helices separated by a hydrophilic segment. Northern blot analysis detected a 4.2-kb mRNA transcript in liver and pancreas, with little expression in all other tissues. In mice, the expressed protein localized to liver mitochondria and varied with changes in dietary protein.
Camacho et al. (1999) mapped the ORNT1 gene to chromosome 13q13-q14.1.
Among 11 patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH syndrome; 238970), Camacho et al. (1999) identified 2 mutations in the ORNT1 gene (see, e.g., phe188del; 603861.0001 and E180K; 603861.0002), and a larger deletion. The phe188del accounted for 19 of 20 possible mutant ORNT1 alleles among French Canadian patients, consistent with a founder effect in that population. Expression of either murine or human ORNT1 restored normal ornithine metabolism in patient-derived fibroblasts.
Tsujino et al. (2000) reported 3 novel mutations in the SLC25A15 gene in Japanese patients with the HHH syndrome.
Miyamoto et al. (2001) reported 2 unrelated Japanese patients who were both homozygous for a nonsense mutation in the SLC25A15 gene (R179X; 603861.0003).
In 8 Italian patients with HHH syndrome, Salvi et al. (2001) identified 9 different mutations in the SLC25A15 gene, 7 of which were novel (see, e.g., 603861.0004).
Debray et al. (2008) noted that 22 different mutations of the SLC25A15 gene had been described in 49 patients from 31 unrelated families with HHH syndrome to date.
In 16 patients from 13 unrelated families with HHH syndrome, Tessa et al. (2009) identified 13 different mutations in the SLC25A15 gene, including 11 novel mutations (see, e.g., 603861.0003; 603861.0006-603861.0008). In vitro functional expression assays showed mutant proteins with decreased transport activity between 4 and 19% of control values. There were no apparent genotype/phenotype correlations.
In 9 of 10 French Canadian patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH syndrome; 238970), Camacho et al. (1999) identified a homozygous 3-bp in-frame deletion in the SLC25A15 gene, resulting in the deletion of phe188 from a sequence of 4 consecutive TTC phenylalanine codons (bp 553-564). in the predicted fourth transmembrane domain. The deletion resulted in an unstable protein. The tenth patient was compound heterozygous for this deletion and a second undetermined allele that has an undetectable transcript. In vitro functional expression studies showed that the F188del mutation resulted in loss of transporter function. The F188del mutant transporter did not target the mitochondria and was not detected in the cytosol, suggesting that this 1-codon deletion impairs stability and/or targeting of the transporter.
In a non-French Canadian patient with HHH (238970), Camacho et al. (1999) identified apparent homozygosity for a 538G-A transition in the SLC25A15 gene, resulting in a glu180-to-lys (E180K) substitution in the predicted fourth transmembrane domain. The patient's Irish American father was an E180K heterozygote, but his Japanese mother was not. These observations, together with the different origins of the 2 parents, indicated that the patient represented a genetic compound for E180K and a second mutant ORNT1 allele that failed to amplify. Further studies suggested that the second allele in this patient carried a microdeletion involving ORNT1 inherited from the mother. The mutant E180K transporter targeted to the mitochondria, but was inactive, indicating that this substitution impairs activity without affecting targeting or stability.
In 2 unrelated Japanese patients with HHH syndrome (238970), Miyamoto et al. (2001) identified a homozygous mutation in the SLC25A15 gene, resulting in an arg179-to-ter (R179X) substitution. One of the patients had been reported by Nakajima et al. (1988).
Tessa et al. (2009) identified homozygosity for the R179X mutation in affected members of 2 unrelated families with HHH syndrome from Senegal and Morocco, respectively. Both children from Senegal had neonatal onset of lethargy and coma. One had pyramidal signs and mild mental retardation, whereas the other had a more severe phenotype with seizures, pyramidal signs, mental retardation, and coagulopathy. In the Moroccan family, 1 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 R179X mutation, had no symptoms by age 4 years.
In a 17-year-old girl with HHH syndrome (238970) since infancy, Salvi et al. (2001) identified a homozygous mutation in the SLC25A15 gene, resulting in a gly27-to-arg (G27R) substitution. The girl was not mentally retarded and did not have spastic paraparesis, but did show pyramidal signs on neurologic examination.
In a 17-year-old girl with HHH syndrome (238970) since the age of 3 years, Salvi et al. (2001) identified a homozygous mutation in the SLC25A15 gene, resulting in an arg275-to-gln (R275Q) substitution.
In a 6-year-old Belgian boy with HHH syndrome (238970) since infancy, Tessa et al. (2009) identified a homozygous 110T-G transversion in exon 3 of the SLC25A15 gene, resulting in a met37-to-arg (M37R) substitution in a transmembrane alpha-helix. The substitution was predicted to interfere with salt bridge formation or protein structure. In vitro functional expression studies showed that the mutant protein had no transport activity. The child had hepatic dysfunction, a coagulopathy, and mild mental retardation, but no other neurologic signs.
In an Italian infant with HHH syndrome (238970), Tessa et al. (2009) identified a homozygous 212T-A transversion in exon 3 of the SLC25A15 gene, resulting in a leu71-to-gln (L71Q) substitution in a transmembrane alpha-helix. The affected residue was predicted to be oriented toward the membrane lipids, which may disturb helix packaging. In vitro functional expression studies showed that the mutant protein had less than 20% residual transport activity. The patient presented in infancy with lethargy and coma, and died at age 2 months.
In a 2-year-old Taiwanese child with HHH syndrome (238970) since infancy, Tessa et al. (2009) identified a homozygous 815C-T transition in exon 7 of the SLC25A15 gene, resulting in a thr272-to-ile (T272I) substitution in a transmembrane alpha-helix. The substitution was predicted to interfere with the formation of crucial bonds due to steric hindrance. In vitro functional expression studies showed that the mutant protein had less than 20% residual transport activity. The patient presented in infancy with lethargy, coma, liver dysfunction, and coagulopathy.
In 5 affected members of 2 related families of Mexican descent with HHH syndrome (238970), Camacho et al. (2006) identified a homozygous C-to-G transversion in exon 3 of the SLC25A15 gene, resulting in a thr32-to-arg (T32R) substitution in a conserved residue in the first hydrophilic loop facing the mitochondrial matrix. The mutation was not found in 116 control individuals. Overexpression studies showed that the mutant protein targeted normally to the mitochondrial and retained some residual activity. However, basal ornithine transport of primary untransfected patient fibroblasts showed loss of function; the observations were important, since they showed a discordance between the clinical and cellular phenotype in patients with HHH syndrome. The patients showed phenotypic variability, with 1 patient in particular having neurologic involvement, including poor school performance, low IQ (55), dysarthria, hyperreflexia, and cortical atrophy on MRI. This patient died from complications of hyperammonemic encephalopathy. The other patients had mild learning disabilities but no neurologic deficits. Two patients with the mildest defects were found to be carriers for a gain of function val181-to-gly (V181G) polymorphism in the ORNT2 gene (SLC25A2; 608157), whereas the members of the family who had the patient with the more severe phenotype had the wildtype val181 ORNT2 variant. The mitochondrial haplotypes of the 2 families also differed. Camacho et al. (2006) suggested that the genotype of HHH patients cannot predict the clinical course of the disease, and that other modifying factors, such as gene redundancy or mitochondrial background may further influence the phenotype.
Camacho, J. A., Mardach, R., Rioseco-Camacho, N., Ruiz-Pesini, E., Derbeneva, O., Andrade, D., Zaldivar, F., Qu, Y., Cederbaum, S. D. Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Pediat. Res. 60: 423-429, 2006. [PubMed: 16940241] [Full Text: https://doi.org/10.1203/01.pdr.0000238301.25938.f5]
Camacho, J. A., Obie, C., Biery, B., Goodman, B. K., Hu, C.-A., Almashanu, S., Steel, G., Casey, R., Lambert, M., Mitchell, G. A., Valle, D. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nature Genet. 22: 151-158, 1999. [PubMed: 10369256] [Full Text: https://doi.org/10.1038/9658]
Debray, F.-G., Lambert, M., Lemieux, B., Soucy, J. F., Drouin, R., Fenyves, D., Dube, J., Maranda, B., Laframboise, R., Mitchell, G. A. Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15. J. Med. Genet. 45: 759-764, 2008. [PubMed: 18978333] [Full Text: https://doi.org/10.1136/jmg.2008.059097]
Miyamoto, T., Kanazawa, N., Kato, S., Kawakami, M., Inoue, Y., Kuhara, T., Inoue, T., Takeshita, K., Tsujino, S. Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X. J. Hum. Genet. 46: 260-262, 2001. [PubMed: 11355015] [Full Text: https://doi.org/10.1007/s100380170075]
Nakajima, M., Ishii, S., Mito, T., Takeshita, K., Takashima, S., Takakura, H., Inoue, I., Saheki, T., Akiyoshi, H., Ichihara, K. Clinical, biochemical and ultrastructural study on the pathogenesis of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Brain Dev. 10: 181-185, 1988. [PubMed: 3407856] [Full Text: https://doi.org/10.1016/s0387-7604(88)80025-1]
Salvi, S., Santorelli, F. M., Bertini, E., Boldrini, R., Meli, C., Donati, A., Burlina, A. B., Rizzo, C., Di Capua, M., Fariello, G., Dionisi-Vici, C. Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Neurology 57: 911-914, 2001. [PubMed: 11552031] [Full Text: https://doi.org/10.1212/wnl.57.5.911]
Tessa, A., Fiermonte, G., Dionisi-Vici, C., Paradies, E., Baumgartner, M. R., Chien, Y.-H., Loguercio, C., de Baulny, H. O., Nassogne, M.-C., Schiff, M., Deodato, F., Parenti, G., and 12 others. Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study. Hum. Mutat. 30: 741-748, 2009. [PubMed: 19242930] [Full Text: https://doi.org/10.1002/humu.20930]
Tsujino, S., Kanazawa, N., Ohashi, T., Eto, Y., Saito, T., Kira, J., Yamada, T. Three novel mutations (G27E, insAAC, R179X) in the ORNT1 gene of Japanese patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. Ann. Neurol. 47: 625-631, 2000. [PubMed: 10805333]