SLC25A15 variants don't translocate ornithine and citrulline

Stable Identifier
R-HSA-9956519
Type
Reaction [transition]
Species
Homo sapiens
Compartment
cytosol, mitochondrial matrix
ReviewStatus
3/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
SLC25A15 variants don't translocate ornithine and citrulline
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
Mutations in SLC25A15 are associated with hyperornithininemia-hyperammonemia-homocitrullinuria (HHH) syndrome (OMIM 238970), an autosomal recessive disorder of the urea cycle characterized by accumulation of citrulline, ornithine and ammonia (Camacho et al, 1999; reviewed in Martinelli et al, 2015). The majority of identified mutations are modelled in the internal pore of the transporter and may affect the translocation of substrate through the membrane. Other mutations affect localization and/or stability of the transporter. Because of the partial redundancy with SLC25A2, the clinical symptoms of HHH are generally milder than those of other urea cycle disorders (reviewed in Martinelli et al, 2015).
The following mutations have been identified in patients with HHH and are largely classified as pathogenic or likely pathogenic in ClinVar. Variants are annotated either as candidates or members depending on the extent of their biochemical characterization:
Candidates:
SLC25A15 T32R (Camacho et al, 2006)
SLC25A15 G113C (Tessa et al, 2009)
SLC25A15 G190D (Salvi Santorelli et al, 2001; Salvi, Dionisi-Vici et al, 2001; Fiermonte et al, 2003)
SLC25A15 T272L (Tessa et al, 2009)
SLC25A15 M273K (Fecarotto et al, 2006; Tessa et al, 2009)

Members:
SLC25A15 A15V (Ersoy Tunali et al, 2014)
SLC25A15 G27R (Salvi, Santorelli et al, 2001; Salvi, Dionisi-Vici et al, 2001; Fiermonte et al, 2003; Tessa et al, 2009)
SLC25A15 M37R (Tessa et al, 2009)
L71Q (Tessa et al, 2009)
SLC25A15 R179* (Miyamoto et al, 2001; Tessa et al, 2009)
SLC25A15 E180K (Camacho et al, 1999)
SLC25A15 F188del (Camacho et al, 1999; Salvi, Santorelli et al, 2001; Salvi, Dionisi-Vici et al, 2001; Fiermonte et al, 2003)
SLC25A15 R275Q (Salvi, Santorelli et al, 2001; Salvi, Dionisi-Vici et al, 2001; Fiermonte et al, 2003; Monne et al, 2012)
SLC25A15 L283F (Tessa et al, 2009)
Literature References
PubMed ID Title Journal Year
22262851 Substrate specificity of the two mitochondrial ornithine carriers can be swapped by single mutation in substrate binding site

Monné, M, Miniero, DV, Daddabbo, L, Robinson, AJ, Kunji, ER, Palmieri, F

J Biol Chem 2012
25874378 The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Martinelli, D, Diodato, D, Ponzi, E, Monné, M, Boenzi, S, Bertini, E, Fiermonte, G, Dionisi-Vici, C

Orphanet J Rare Dis 2015
19242930 Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study

Tessa, A, Fiermonte, G, Dionisi-Vici, C, Paradies, E, Baumgartner, MR, Chien, YH, Loguercio, C, de Baulny, HO, Nassogne, MC, Schiff, M, Deodato, F, Parenti, G, Rutledge, SL, Vilaseca, MA, Melone, MA, Scarano, G, Aldamiz-Echevarría, L, Besley, G, Walter, J, Martinez-Hernandez, E, Hernandez, JM, Pierri, CL, Palmieri, F, Santorelli, FM

Hum Mutat 2009
16601889 HHH syndrome (hyperornithinaemia, hyperammonaemia, homocitrullinuria), with fulminant hepatitis-like presentation

Fecarotta, S, Parenti, G, Vajro, P, Zuppaldi, A, Della Casa, R, Carbone, MT, Correra, A, Torre, G, Riva, S, Dionisi-Vici, C, Santorelli, FM, Andria, G

J Inherit Metab Dis 2006
24721342 A novel mutation in the SLC25A15 gene in a Turkish patient with HHH syndrome: functional analysis of the mutant protein

Ersoy Tunalı, N, Marobbio, CM, Tiryakioğlu, NO, Punzi, G, Saygılı, SK, Onal, H, Palmieri, F

Mol Genet Metab 2014
10369256 Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter.

Camacho, JA, Obie, C, Biery, B, Goodman, BK, Hu, CA, Almashanu, S, Steel, G, Casey, R, Lambert, M, Mitchell, GA, Valle, D

Nat Genet 1999
12807890 The mitochondrial ornithine transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms

Fiermonte, G, Dolce, V, David, L, Santorelli, FM, Dionisi-Vici, C, Palmieri, F, Walker, JE

J Biol Chem 2003
11552031 Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Salvi, S, Santorelli, FM, Bertini, E, Boldrini, R, Meli, C, Donati, A, Burlina, AB, Rizzo, C, Di Capua, M, Fariello, G, Dionisi-Vici, C

Neurology 2001
11668643 Seven novel mutations in the ORNT1 gene (SLC25A15) in patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome

Salvi, S, Dionisi-Vici, C, Bertini, E, Verardo, M, Santorelli, FM

Hum Mutat 2001
11355015 Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X

Miyamoto, T, Kanazawa, N, Kato, S, Kawakami, M, Inoue, Y, Kuhara, T, Inoue, T, Takeshita, K, Tsujino, S

J Hum Genet 2001
Participants
Input
Participates
as an event of
Catalyst Activity

L-ornithine transmembrane transporter activity of SLC25A15 variants [mitochondrial inner membrane]

Physical Entity
SLC25A15 variants [mitochondrial inner membrane] (Homo sapiens)
Activity
L-ornithine transmembrane transporter activity (GO:0000064)
Normal reaction
ornithine (cytosolic) + citrulline (mitochondrial) => ornithine (mitochondrial) + citrulline (cytosolic) (Homo sapiens)
Functional status

Loss of function of SLC25A15 variants [mitochondrial inner membrane]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
ornithine translocase deficiency DOID:0050720 Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome, HHH syndrome
Cross References
Mondo
Authored
Rothfels, K  (2025-07-02)
Created
Rothfels, K  (2025-06-12)
Cite Us!