A Gain-of-Function Mutation on BCKDK Gene and Its Possible Pathogenic Role in Branched-Chain Amino Acid Metabolism

Abstract

BCKDK is an important key regulator of branched-chain ketoacid dehydrogenase complex activity by phosphorylating and so inactivating branched-chain ketoacid dehydrogenases, the rate-limiting enzyme of the branched-chain amino acid metabolism. We identified, by whole exome-sequencing analysis, the p.His162Gln variant of the BCKDK gene in a neonate, picked up by newborn screening, with a biochemical phenotype of a mild form of maple syrup urine disease (MSUD). The same biochemical and genetic picture was present in the father. Computational analysis of the mutation was performed to better understand its role. Extensive atomistic molecular dynamics simulations showed that the described mutation leads to a conformational change of the BCKDK protein, which reduces the effect of inhibitory binding bound to the protein itself, resulting in its increased activity with subsequent inactivation of BCKDC and increased plasmatic branched-chain amino acid levels. Our study describes the first evidence of the involvement of the BCKDK gene in a mild form of MSUD. Although further data are needed to elucidate the clinical relevance of the phenotype caused by this variant, awareness of this regulatory activation of BCKDK is very important, especially in newborn screening data interpretation.

The Role of Branched-Chain Amino Acids and Branched-Chain α-Keto Acid Dehydrogenase Kinase in Metabolic Disorders

“…Nowadays, there is a great progress in the detection of amino acids at very low concentrations in complex matrixes, including liquid chromatography-mass spectrometry (LC-MS) and capillary electrophoresis-mass spectrometry (CE-MS) (6,8,9). Liquid chromatography and tandem mass spectrometry appear to be the major methods for detecting plasma BCAAs nowadays (10)(11)(12)(13).…”

“…BCKAs especially the KIC allosterically regulate BCKDK. If the BCKAs are at high concentration, BCKAs will inhibit the activity of BCKDK, preventing BCAAs from running out when they are at low concentration ( 6 ). However, BCKDK also seems to be regulated by the BCKDH complex, the details of the mechanism need to be studied ( 6 ).…”

“…If the BCKAs are at high concentration, BCKAs will inhibit the activity of BCKDK, preventing BCAAs from running out when they are at low concentration ( 6 ). However, BCKDK also seems to be regulated by the BCKDH complex, the details of the mechanism need to be studied ( 6 ). The dephosphorylation process which activates the BCKDH complex is catalyzed by mitochondrial phosphatase 2C (PP2Cm).…”

PPM1K defects cause mild maple syrup urine disease: The second case in the literature

“…Recently, a newborn with a biochemical phenotype suggestive of MSUD with a heterozygous gain-of-function BCKDK variant was reported. The asymptomatic father and grandfather also carried the same variant (Maguolo et al, 2022). In addition, Oyarzabal et al discovered a homozygous truncating variant in PPM1K in a 21-year-old woman with mild MSUD (Oyarzabal et al, 2013).…”

Structural studies identify angiotensin II receptor blocker-like compounds as branched-chain ketoacid dehydrogenase kinase inhibitors

“…This disease is characterized by the accumulation of BCKA and BCAA in plasma and urine, which has severe clinical consequences, including often fatal acidosis, neurological derangement, and developmental delay ( 20 ). Recently, a gain-of-function BCKDK variant with a single mutation at its physiological ligand-binding site was reported to be associated with a mild form of maple syrup urine disease ( 21 ). Recent metabolomics studies have further reported that elevated blood BCAA concentration is associated with insulin resistance and nonalcoholic fatty liver disease ( 22 , 23 , 24 , 25 ).…”