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

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.

A Japanese case of mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase deficiency who presented with severe metabolic acidosis and fatty liver without hypoglycemia

“…7 To date, more than 20 cases have been reported. [8][9][10][11][12][13][14][15][16][17] Most patients presented with hypoglycemia and hepatomegaly during acute infection and prolonged fasting and showed an absence of clinical symptoms in the intermittent phase. Non-(hypo)-ketotic hypoglycemia with high free fatty acids (FFA) is the predominant laboratory finding.…”

Novel HMGCS2 pathogenic variants in a Chinese family with mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase deficiency

“…The phenotypic expression of different mitochondrial HMG‐CoA synthase deficiency mutants in patients varies considerably. Of the reported HMGCS2 variants, most (24/31) are missense variants which lead to decreases in gene expression or enzymatic activity levels . Truncating variants usually cause early degradation of the mRNA transcript through nonsense‐mediated decay, leading to undetectable enzymatic activity.…”

“…Of the reported HMGCS2 variants, most (24/31) are missense variants which lead to decreases in gene expression or enzymatic activity levels. 1 Truncating variants usually cause early degradation of the mRNA transcript through nonsense-mediated decay, leading to undetectable enzymatic activity. Our case is the first report of a patient carrying two truncating variants.…”

“…Mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA (HMG‐CoA) synthase deficiency (OMIM #605911) is a rare and underdiagnosed disorder, with fewer than 30 patients reported worldwide . It is characterized by hypoketotic hypoglycemia, encephalopathy, and hepatomegaly.…”

The gene encoding the ketogenic enzyme HMGCS2 displays a unique expression during gonad development in mice

“…Homozygous variants in human HMGCS2 are well known to cause the very rare metabolic disorder HMGCS2 deficiency [24] (OMIM: 605911), which is characterized by severe hypoketotic hypoglycemia, encephalopathy, and hepatomegaly that is triggered after extended periods of fasting or after infections [28]. To date, 27 HMGCS2 deficiency patients have been identified including ten males, three females, and 14 patients for which the sex was not reported [24][25][26][27][28][57][58][59][60][61]. However, gonadal defects have not yet been described in any of these patients who carry homozygous or compound heterozygous HMGCS2 variants.…”