Disease relevance of SLC25A15

• Seven novel mutations in the ORNT1 gene (SLC25A15) in patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome [1].
• Patients with mitochondrial ornithine transporter deficiency (or HHH syndrome) present with various neurological symptoms, including mental retardation, spastic paraparesis with pyramidal signs, cerebellar ataxia, and episodic disturbance of consciousness or coma due to hyperammonemia [2].
• Mitochondrial ornithine transporter deficiency, or HHH syndrome, is a metabolic 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 [3].
• BACKGROUND AND PURPOSE: Patients with hemiparesis, hemisensory loss, and hemianopsia ("HHH" deficits) due to stroke may have large cortical lesions caused by middle cerebral trunk vessel occlusion or smaller subcortical lesions due to lenticulostriate involvement [4].
• The patient required HHH therapy with a very high blood pressure to optimize her clinical neurologic status, but she started to develop pulmonary edema resulting from this therapy [5].

Psychiatry related information on SLC25A15

• In this article, we report a new patient with HHH syndrome, a 52-year-old woman, who had the typical clinical features, except for an absence of mental retardation [2].
• Individuals scoring high in the need for Power (n Power), in inhibition, and in the number of power stresses (HHH subjects), reported more severe physical illness and affective symptoms than all other subjects or, in particular, subjects low in n Power, power stress and inhibition (LLL subjects) [6].

High impact information on SLC25A15

• ORNT1 expression restores ornithine metabolism in fibroblasts from patients with hyperammonaemia-hyperornithinaemia-homocitrullinuria (HHH) syndrome [7].
• Three novel mutations (G27E, insAAC, R179X) in the ORNT1 gene of Japanese patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome [8].
• The ORNT1 gene consists of at least six exons, and all exon-intron junction sequences conform to the GT/AG rule [8].
• We report three novel mutations in the mitochondrial ornithine transporter gene (ORNT1) of Japanese patients with HHH syndrome: a nonsense mutation (R179X) associated with exon skipping and a frameshift, a missense mutation (G27E), and an insertion of AAC between codons 228 and 229, leading to an insertion of the amino acid Asn [8].
• Discrete aggregates of distended hepatocytes with central nuclei and nonvacuolated clear cytoplasm were present in 5 of the 10 children, including two 2 OTC deficiency, 2 with CPS deficiency, and 1 with HHH [9].

Chemical compound and disease context of SLC25A15

• Mutations in the mitochondrial ornithine transporter result in hyperammonemia, hyperornithinemia, homocitrullinuria syndrome, a disorder of the urea cycle [10].
• The primary defect in patients presenting with a history of protein intolerance, mental retardation, and epilepsy of variable degree, with the unique triad of hyperornithinemia, hyperammonemia, and homocitrullinuria (the HHH syndrome) has been postulated to be a defect in translocation of ornithine into the mitochondria [11].

Biological context of SLC25A15

• These observations suggest that the ORNT1 genotype cannot predict the phenotype of HHH patients [12].
• The clinical features of previously documented patients with the homozygous SLC25A15 mutation demonstrated that genotype did not simply correlate with clinical severity [13].
• The mitochondrial ornithine transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms [14].
• Using conserved sequences of mammalian and fungal mitochondrial ornithine transporters, we screened the Expressed Sequence Tag database for additional transporters belonging to the ORNT subfamily [15].
• Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X [2].

Anatomical context of SLC25A15

• Ornithine transport studies in HHH015 fibroblasts, however, showed basal activity similar to fibroblasts carrying nonfunctional ORNT1 alleles [12].
• The use of yeast mitochondria to study the properties of wild-type and mutant human mitochondrial ornithine transporter [10].
• Given that the inner mitochondrial membrane is impermeable to solutes, we hypothesize that other unidentified carriers have some degree of functional redundancy with ORNT1 [15].
• These findings are indicative of mitochondrial dysfunction and are in accordance with ultrastructural studies showing increased numbers of large and bizarre mitochondria in liver, muscle, leukocytes and fibroblasts of some HHH patients [16].
• We have analyzed ornithine transport activities in the liver mitochondria from three patients with HHH disorder [17].

Associations of SLC25A15 with chemical compounds

• We recently characterized the mitochondrial ornithine transporter (ORNT1), the gene defective in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, a urea cycle disorder [15].
• These results are used as reference values to which are compared values obtained from pregnancies at risk for citrullinaemia, argininosuccinic aciduria, HHH (hyperornithinaemia, hyperammonaemia and homocitrullinaemia) syndrome, cobalamin metabolism disorders (CblC or CblD), and sulphite oxidase deficiency [18].
• More of the HHH than other subjects also showed above average epinephrine excretion rates in urine and below average concentrations of immunoglobulin A in saliva (S-IgA) [19].

Other interactions of SLC25A15

• The gene product of ORNT2 is 88% identical to ORNT1, targets to the mitochondria and is expressed in human liver, pancreas, kidney, and cultured fibroblasts from control and HHH patients [15].
• We subsequently studied distal deletions using the D13S25 probe (13q14.3) and a subtelomeric probe (13qSTP) for the 13q-arm (D13S327) in 40 cases with documented LSI 13 (Rb)/D13S319 deletion and 40 without deletion of these loci [20].

Analytical, diagnostic and therapeutic context of SLC25A15

• Direct sequencing of the PCR products of SLC25A15 exon amplifications revealed that both brothers were homozygous for a novel 446G deletion in exon 3 as well as for a 760A>T (I254L) polymorphism in exon 5, which is downstream of a premature termination codon produced by the frameshift resulting from the 446G deletion [16].
• Clinical trials update from the joint European Society and World Congress of Cardiology meeting: PEP-CHF, ACCLAIM and the HHH study [21].
• The common therapeutic approach to patients, who develop vasospasm following subarachnoid hemorrhage, is usually composed of hypertension, hypervolemia, and hemodilution (HHH) [5].

References