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Open AccessArticle

Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients

Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, E-50009 Zaragoza, Spain
Molecular Modelling Group, Center of Molecular Biology “Severo Ochoa” (CSIC-UAM), Cantoblanco, E-28049 Madrid, Spain
Faculty of Experimental Sciences, Francisco de Vitoria University, Pozuelo de Alarcón, 28223 Madrid, Spain
Division of Medical Genetics, Department of Medicine, CHUM (Centre Hospitalier Universitaire de l’Université de Montréal) and Université de Montréal, Montreal, QC H2X 0A9, Canada
Willink Metabolic Unit, Manchester Centre for Genomic Medicine, Saint Mary’s Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK
Hôpital Universitaire des Enfants Reine Fabiola, Avenue Crocq 15, B-1020 Brussels, Belgium
Centre Hospitalier Universitaire de Québec, Québec City, QC G1V 4G2, Canada
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(4), 1010;
Received: 27 February 2018 / Revised: 23 March 2018 / Accepted: 26 March 2018 / Published: 28 March 2018
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies)
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mitochondrial HMG-CoA synthase deficiency or mHS deficiency, OMIM #605911) is an inborn error of metabolism that affects ketone body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycemia and dicarboxylic aciduria. The diagnosis is difficult due to the relatively unspecific clinical and biochemical presentation, and fewer than 30 patients have been described. This work describes three new patients with mHS deficiency and two missense mutations c.334C>T (p.R112W) and c.430G>T (p.V144L) previously not reported. We developed a new method to express and measure the activity of the enzyme and in this work the study is extended to ten new missense variants including those of our patients. Enzymatic assays showed that three of the mutant proteins retained some but seven completely lacked activity. The identification of a patient homozygous for a mutation that retains 70% of enzyme activity opens the door to a new interpretation of the disease by demonstrating that a modest impairment of enzyme function can actually produce symptoms. This is also the first study employing molecular dynamics modelling of the enzyme mutations. We show that the correct maintenance of the dimerization surface is crucial for retaining the structure of the active center and therefore the activity of the enzyme. View Full-Text
Keywords: mitochondrial HMG-CoA synthase; deficiency; mutations; enzyme dimerization; ketone bodies mitochondrial HMG-CoA synthase; deficiency; mutations; enzyme dimerization; ketone bodies
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Puisac, B.; Marcos-Alcalde, I.; Hernández-Marcos, M.; Tobajas Morlana, P.; Levtova, A.; Schwahn, B.C.; DeLaet, C.; Lace, B.; Gómez-Puertas, P.; Pié, J. Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients. Int. J. Mol. Sci. 2018, 19, 1010.

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