Mysm1 mutations in meander tail mice cause anterior-selective cerebellum malformation

The anterior cerebellum defects are cell autonomous with respect to granule cell precursors, but the molecular basis has not been known. Myb-like, SWIRM, and MPN domain containing protein 1 (MYSM1) is a chromatin-associated deubiquitinase that promotes gene expression by removing monoubiquitin from histone H2A, among other targets.

Loss of MYSM1 function in mice or humans results in bone marrow failure with defective maturation of B cell lineages. Here we show that extant mea alleles have mutations in Mysm1 and cause both neurological and hematological phenotypes, as do new endonuclease-mediated mutations. Multimodal single-nucleus assays show Mysm1 effects on gene expression in several lineages and on the proportion of granule cell precursors by E14.5.