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

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 aci...

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Autores principales: Puisac, Beatriz, Marcos-Alcalde, Iñigo, Hernández-Marcos, María, Tobajas Morlana, Pilar, Levtova, Alina, Schwahn, Bernd C., DeLaet, Corinne, Lace, Baiba, Gómez-Puertas, Paulino, Pié, Juan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979369/
https://www.ncbi.nlm.nih.gov/pubmed/29597274
http://dx.doi.org/10.3390/ijms19041010
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author Puisac, Beatriz
Marcos-Alcalde, Iñigo
Hernández-Marcos, María
Tobajas Morlana, Pilar
Levtova, Alina
Schwahn, Bernd C.
DeLaet, Corinne
Lace, Baiba
Gómez-Puertas, Paulino
Pié, Juan
author_facet Puisac, Beatriz
Marcos-Alcalde, Iñigo
Hernández-Marcos, María
Tobajas Morlana, Pilar
Levtova, Alina
Schwahn, Bernd C.
DeLaet, Corinne
Lace, Baiba
Gómez-Puertas, Paulino
Pié, Juan
author_sort Puisac, Beatriz
collection PubMed
description 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.
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spelling pubmed-59793692018-06-10 Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients Puisac, Beatriz Marcos-Alcalde, Iñigo Hernández-Marcos, María Tobajas Morlana, Pilar Levtova, Alina Schwahn, Bernd C. DeLaet, Corinne Lace, Baiba Gómez-Puertas, Paulino Pié, Juan Int J Mol Sci Article 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. MDPI 2018-03-28 /pmc/articles/PMC5979369/ /pubmed/29597274 http://dx.doi.org/10.3390/ijms19041010 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Puisac, Beatriz
Marcos-Alcalde, Iñigo
Hernández-Marcos, María
Tobajas Morlana, Pilar
Levtova, Alina
Schwahn, Bernd C.
DeLaet, Corinne
Lace, Baiba
Gómez-Puertas, Paulino
Pié, Juan
Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients
title Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients
title_full Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients
title_fullStr Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients
title_full_unstemmed Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients
title_short Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients
title_sort human mitochondrial hmg-coa synthase deficiency: role of enzyme dimerization surface and characterization of three new patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979369/
https://www.ncbi.nlm.nih.gov/pubmed/29597274
http://dx.doi.org/10.3390/ijms19041010
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