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Am J Hum Genet. 2017 Apr 6;100(4):617-634. doi: 10.1016/j.ajhg.2017.03.005. Epub 2017 Mar 30.

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes.

Author information

1
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
2
New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
3
Departments of Neurology and Neuroscience, College of Medicine and Life Science, University of Toledo, Toledo, OH 43614, USA.
4
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
5
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Neuroscience, Faculty of Medicine and Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
6
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA; Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; Department of Pediatrics, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
7
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: paul.tesar@case.edu.

Abstract

Pelizaeus-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.

KEYWORDS:

PLP1; PMD; Pelizaeus-Merzbacher disease; endoplasmic reticulum stress; genotype-phenotype correlation; hiPSC; human induced pluripotent stem cell; leukodystrophy; myelin; oligodendrocyte; proteolipid protein 1

PMID:
28366443
PMCID:
PMC5384098
DOI:
10.1016/j.ajhg.2017.03.005
[Indexed for MEDLINE]
Free PMC Article

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