Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients.
Author: Puisac, Beatriz; Marcos Alcalde, Íñigo; Hernández Marcos, María; Tobajas Morlana, Pilar; Levtova, Alina; C. Schwahn, Bernd; DeLaet, Corinne; Lace, Baiba; Gómez Puertas, Paulino; Pié, Juan
Abstract: 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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