Genetic basis of mitochondrial HMG-CoA synthase deficiency

Abstract

Deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHMGS) is a recessive disorder of ketogenesis that has been previously diagnosed in two children with hypoglycaemic hypoketotic coma during fasting periods. Here, we report the results of molecular investigations in a third patient affected by this disease. Sequencing of the entire coding region of the HMGCS2 gene revealed two missense mutations, G212R and R500H. Mendelian inheritance was confirmed by the analysis of parental samples and neither of the mutations was found on 200 control chromosomes. Functional relevance was confirmed by in vitro expression studies in cytosolic HMGS-deficient cells. Whereas wild-type cDNA of the HMGCS2 gene reverted the auxotrophy for mevalonate, the cDNAs of the mutants did not. The disease may be recognised by specific clinical and biochemical features but it is difficult to confirm enzymatically since the gene is expressed only in liver and testis. Molecular studies may facilitate or confirm future diagnoses in affected patients.

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

“…Variations in the genes encoding ketogenic mediators, including HMGCS2, HMG-CoA lyase, and βOHB dehydrogenase, have not yet emerged as independent predictors of liver pathology or diabetes. While HMGCS2 deficiency is very rare in humans, total HMGCS2 enzymatic deficiency is associated with pediatric hypoketonemic hypoglycemia and hepatic steatosis (66)(67)(68)(69)(70)(71). Importantly, our studies of neonatal mice revealed that partial loss of HMGCS2 activity caused marked hepatic steatosis vastly out of proportion to the diminution in neonatal ketosis, but did not result in neonatal hypoglycemia or failure to thrive.…”

Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure

“…The GO terms included genes for carnitine palmitoyltransferase I ( CPT1 ), 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (CoA) synthase 2 ( HMGCS2 ), and 3‐oxoacid CoA‐transferase 1 ( OXCT1 ), which are known to play important roles in generating energy in cells and tissues 13, 14, 15…”

“…The KEGG pathway analysis showed that the genes related to butanoate metabolism were down‐regulated in the thin endometrium. Genes, such as CPT1 , HMGCS2 , and OXCT1 , are essential for generating acetyl‐CoA and ketone bodies in butanoate metabolism 13, 14, 15. Butanoate is a substrate that is used to generate energy in both aerobic and anaerobic processes.…”

Impact of Peripheral Ketolytic Deficiency on Hepatic Ketogenesis and Gluconeogenesis during the Transition to Birth

“…Case reports indicate that HMGCS2-and SCOT-deficient humans adapt poorly to nutrient states that are marked by diminished carbohydrate intake. Human HMGCS2 deficiency results in pediatric hypoketonemic hypoglycemia (42), and human CoA transferase deficiency manifests as spontaneous pediatric ketoacidosis (43,44), which in severe cases is associated with hypoglycemia and may account for a subset of idiopathic ketotic hyopoglycemia cases (45,46). SCOT-KO mice die in a manner that mimics human sudden infant death syndrome (SIDS)/sudden unexpected death in infancy (SUDI), the leading cause of death of U.S. infants after the age of 1 month (47).…”