A novel mutation in the SLC25A15 gene in a Turkish patient with HHH syndrome: Functional analysis of the mutant protein
| Autor: | Ferdinando Palmieri, N. Ozan Tiryakioglu, Giuseppe Punzi, Hasan Önal, Carlo M.T. Marobbio, Seha Saygili, Nagehan Ersoy Tunali |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Endocrinology Diabetes and Metabolism DNA Mutational Analysis Biology medicine.disease_cause Biochemistry Mitochondrial Membrane Transport Proteins Article chemistry.chemical_compound Endocrinology Mutant protein Genetics medicine Hyperammonemia Homocitrullinuria Humans Point Mutation Child Molecular Biology Urea Cycle Disorders Inborn Hyperornithinemia Mitochondrial ornithine carrier Mutation Cerebellar ataxia Point mutation HHH syndrome Ornithine medicine.disease Mitochondria chemistry Ornithine transport Amino Acid Transport Systems Basic medicine.symptom SLC25A15 Sequence Alignment |
| Zdroj: | Molecular Genetics and Metabolism |
| ISSN: | 1096-7206 1096-7192 |
| Popis: | 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. Highlights • A novel mutation in SLC25A15 encoding the ornithine carrier ORC1 was identified. • The new variant was found in a Turkish child presenting the symptoms of HHH syndrome. • The patient was homozygous and the healthy parents heterozygous for the new mutation. • The functional defect of the mutant protein was proven by two different methods. • Complementing of the yeast ORT1∆ was applied to HHH patients for the first time. |
| Databáze: | OpenAIRE |
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