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dc.contributor.authorPuisac, Beatriz
dc.contributor.authorMarcos Alcalde, Íñigo 
dc.contributor.authorHernández Marcos, María
dc.contributor.authorTobajas Morlana, Pilar
dc.contributor.authorLevtova, Alina
dc.contributor.authorC. Schwahn, Bernd
dc.contributor.authorDeLaet, Corinne
dc.contributor.authorLace, Baiba
dc.contributor.authorGómez Puertas, Paulino
dc.contributor.authorPié, Juan
dc.description.abstractMitochondrial 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
dc.publisherInternational Journal of Molecular Sciencesspa
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 España*
dc.subjectMitochondrial HMG-CoA synthasespa
dc.subjectEnzyme dimerizationspa
dc.subjectKetone bodiesspa
dc.titleHuman Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New
dc.description.extent1746 KBspa

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Atribución-NoComercial-SinDerivadas 3.0 España
Except where otherwise noted, this item's license is described as Atribución-NoComercial-SinDerivadas 3.0 España