02588nas a2200253   4500000000100000008004100001260001400042100002100056700002100077700001900098700002400117700001800141700002200159700002200181700002200203700002000225700001800245245012700263856005800390300001200448490000800460520185200468022001402320       2017                            d  c2017-4-061 aZachary S. Nevin1 aDaniel C. Factor1 aRobert T. Karl1 aPanagiotis Douvaras1 aJeremy Laukka1 aMartha S. Windrem1 aSteven A. Goldman1 aValentina Fossati1 aGrace M. Hobson1 aPaul J. Tesar00aModeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes  uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384098/  a617-6340 v1003 aPelizaeus-Merzbacher disease (PMD) is a pediatric disease of myelin in the central nervous system and manifests with a wide spectrum of clinical severities. Although PMD is a rare monogenic disease, hundreds of mutations in the X-linked myelin gene proteolipid protein 1 (PLP1) have been identified in humans. Attempts to identify a common pathogenic process underlying PMD have been complicated by an incomplete understanding of PLP1 dysfunction and limited access to primary human oligodendrocytes. To address this, we generated panels of human induced pluripotent stem cells (hiPSCs) and hiPSC-derived oligodendrocytes from 12 individuals with mutations spanning the genetic and clinical diversity of PMD—including point mutations and duplication, triplication, and deletion of PLP1—and developed an in vitro platform for molecular and cellular characterization of all 12 mutations simultaneously. We identified individual and shared defects in PLP1 mRNA expression and splicing, oligodendrocyte progenitor development, and oligodendrocyte morphology and capacity for myelination. These observations enabled classification of PMD subgroups by cell-intrinsic phenotypes and identified a subset of mutations for targeted testing of small-molecule modulators of the endoplasmic reticulum stress response, which improved both morphologic and myelination defects. Collectively, these data provide insights into the pathogeneses of a variety of PLP1 mutations and suggest that disparate etiologies of PMD could require specific treatment approaches for subsets of individuals. More broadly, this study demonstrates the versatility of a hiPSC-based panel spanning the mutational heterogeneity within a single disease and establishes a widely applicable platform for genotype-phenotype correlation and drug screening in any human myelin disorder.  a0002-9297