H139Hfs13* PPM1K causes a mild variant of MSUD

BCKDH is responsible for the oxidative decarboxylation of branched-chain amino acid (BCAA) derivatives of leucine, valine and isoleucine, providing acetyl CoA and succinyl CoA intermediates for the Krebs Cycle (reviewed in Strauss et al, 2020; Zhang et al, 2023). Loss-of-function mutations in subunits of BCKDH cause accumulation of toxic BCAAs in the urine, neurological defects and are the cause of Maple Syrup Urine disease (MSUD). More recently, a frameshift mutation in PPM1K was identified as the probable cause of a mild variant of MSUD. This frameshift introduces a stop codon at residue 151, destabilizing the protein, and transfection of PPM1K-deficient fibroblast lines with WT PPM1K restores BCKDH activity.