CRAT missense variants cause abnormal carnitine acetyltransferase function in an early-onset case of Leigh syndrome
| Autor: | Giuseppe Punzi, Luna Laera, Vito Porcelli, Lucia Trisolini, Nicola Gambacorta, Anna De Grassi, Ciro Leonardo Pierri |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular Neurodegeneration with brain iron accumulation Protein Conformation DNA Mutational Analysis Mutation Missense Biology 03 medical and health sciences Structure-Activity Relationship Carnitine Acetyltransferase Genetics Missense mutation Humans Binding site Age of Onset Gene Genetics (clinical) 030304 developmental biology chemistry.chemical_classification 0303 health sciences Carnitine O-Acetyltransferase Binding Sites 030305 genetics & heredity Enzyme Activation Enzyme chemistry Mitochondrial encephalopathy Leigh Disease Function (biology) Protein Binding |
| Zdroj: | Human mutation. 41(1) |
| ISSN: | 1098-1004 |
| Popis: | Leigh syndrome, or subacute necrotizing encephalomyelopathy, is one of the most severe pediatric disorders of the mitochondrial energy metabolism. By performing whole-exome sequencing in a girl affected by Leigh syndrome and her parents, we identified two heterozygous missense variants (p.Tyr110Cys and p.Val569Met) in the carnitine acetyltransferase (CRAT) gene, encoding an enzyme involved in the control of mitochondrial short-chain acyl-CoA concentrations. Biochemical assays revealed carnitine acetyltransferase deficiency in the proband-derived fibroblasts. Functional analyses of recombinant-purified CRAT proteins demonstrated that both missense variants, located in the acyl-group binding site of the enzyme, severely impair its catalytic function toward acetyl-CoA, and the p.Val569Met variant also toward propionyl-CoA and octanoyl-CoA. Although a single recessive variant in CRAT has been recently associated with neurodegeneration with brain iron accumulation (NBIA), this study reports the first kinetic analysis of naturally occurring CRAT variants and demonstrates the genetic basis of carnitine acetyltransferase deficiency in a case of mitochondrial encephalopathy. |
| Databáze: | OpenAIRE |
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