Deficiency in branched-chain alpha-ketoacid dehydrogenase (BCKDH) causes maple syrup urine disease (MSUD), which has both acute and long-term neurotoxicity. The pathology of MSUD is attributed mainly to branched-chain amino acid (BCAA) accumulation, but BCAA normalized patients still show chronic neuropsychological problems. BCKDH is comprised of three subunits, E1, E2 and E3. Here we show that Caenorhabditis elegans gene ZK669.4 encodes an orthologue of human DBT (E2 subunit). A loss of function mutation in ZK669.4,
ok3001, causes BCAA accumulation resembling MSUD but also leads to monomethyl branched-chain fatty acid (mmBCFA) deficiency.
ok3001 worms manifest larval arrest and embryonic lethal phenotypes and mmBCFA supplementation suppresses both without correcting BCAA levels. The majority of developmental defects caused by BCKDH deficiency may thus be attributed to lacking mmBCFAs in worms. Tissue-specific analysis shows that restoration of BCKDH function in multiple tissues can rescue the defects, but is especially effective in neurons. The larval arrest phenotype of
ok3001 is due to a lack of
d17SPA, a C15ISO containing sphingolipid critical for larval development. The embryonic phenotype is not due to a lack of
d17SPA but is possibly caused by a deficiency of mmBCFA containing phospholipids which leads to egg shell defects and cytokinesis failure in the early embryo. Our result shows that mmBCFAs play multiple, critical roles in the development of C. elegans and disruption of BCKDH affects mmBCFA biosynthesis, which has detrimental consequences. Taken together, we propose that mmBCFAs, which are present in humans but with no known function, may contribute to the pathology, especially the neurotoxicity of MSUD.