A novel mutation in the SLC25A15 gene in a Turkish patient with HHH syndrome: functional analysis of the mutant protein.
The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome is a rare autosomal recessive disorder caused by the functional deficiency of the mitochondrial ornithine transporter 1 (ORC1). ORC1 is encoded by the SLC25A15 gene and catalyzes the transport of cytosolic ornithine into mitochondria in exchange for citrulline. Although the age of onset and the severity of the symptoms vary widely, the disease usually manifests in early infancy. The typical clinical features include protein intolerance, lethargy, episodic confusion, cerebellar ataxia, seizures and mental retardation. In this study, we identified a novel p.Ala15Val (c.44C>T) mutation by genomic DNA sequencing in a Turkish child presenting severe tantrum, confusion, gait disturbances and loss of speech abilities in addition to hyperornithinemia, hyperammonemia and homocitrullinuria. One hundred Turkish control chromosomes did not possess this variant. The functional effect of the novel mutation was assessed by both complementation of the yeast ORT1 null mutant and transport assays. Our study demonstrates that the A15V mutation dramatically interferes with the transport properties of ORC1 since it was shown to inhibit ornithine transport nearly completely.
Department of Molecular Biology and Genetics, Haliç University, Istanbul, Turkey. Electronic address: nagehanersoy@halic.edu.tr.
Nagehan
N
Ersoy Tunalı
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
Carlo M T
CM
Marobbio
Department of Molecular Biology and Genetics, Haliç University, Istanbul, Turkey.
N Ozan
NO
Tiryakioğlu
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
Giuseppe
G
Punzi
Istanbul Medical Faculty, Department of Pediatrics, Istanbul University, Istanbul, Turkey.
Seha K
SK
Saygılı
Department of Pediatric Metabolism and Nutrition, Kanuni Sultan Süleyman Research and Training Hospital, Istanbul, Turkey.
Hasan
H
Onal
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy. Electronic address: ferdinando.palmieri@uniba.it.
Ferdinando
F
Palmieri
D026923:Amino Acid Transport Systems, Basic / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D004252:DNA Mutational Analysis; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins; D017354:Point Mutation; D016415:Sequence Alignment; D056806:Urea Cycle Disorders, Inborn / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology
D026923:Amino Acid Transport Systems, Basic; D033681:Mitochondrial Membrane Transport Proteins; C442901:SLC25A15 protein, human
HHH syndrome; Homocitrullinuria; Hyperammonemia; Hyperornithinemia; Mitochondrial ornithine carrier; SLC25A15