LAUSR

Loss-of-function mutations in PYCR2 cause hypomyelinating leukodystrophy 10 (HLD10) (MIM: 616420) characterized by postnatal degenerative microcephaly, severely delayed psychomotor development, and hypomyelination. Here, we report 3 additional patients with a novel germline homozygous missense G249V, which lies at the PYCR2 dimer interface and lowers its enzymatic activity. PYCR2 is a mitochondrial enzyme essential for proline synthesis but its function in the brain is not yet understood. We generated Pycr2-/mice that partly recapitulate the human phenotype by displaying a failure to thrive, reduced lifespan, postnatal neurological defects and hypomyelination. Consistent with this, we show that PYCR2 is broadly expressed in mouse brain tissues and its loss leads to neuronal and oligodendrocytes maturation defects. To further delineate the function of PYCR2, metabolites related to amino-acid biosynthesis and key neurotransmitters were quantified directly in mouse brain. Unexpectedly, the only difference detected was a robust increase in glycine levels. Intriguing, hyperglycinemia is also a hallmark of glycine encephalopathy, a genetic disorder which causes severe neurological symptoms. Furthermore, we demonstrate in mouse brain and human cells that PYCR2 regulates the level of SHMT2, the mitochondrial enzyme responsible for glycine synthesis. Our findings reveal that PYCR2 is an enzyme with moonlighting potential, essential to control white matter and neuronal postnatal development and identify the SHMT2 pathway as a potential target to treat neurological disorder due to the loss of PYCR2.