1. yippee like 3 (ypel3) is a novel gene required for myelinating and perineurial glia development
- Author
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Bernardo Blanco-Sánchez, Aurélie Clément, Sara J Stednitz, Jennifer Kyle, Judy L Peirce, Marcie McFadden, Jeremy Wegner, Jennifer B Phillips, Ellen Macnamara, Yan Huang, David R Adams, Camilo Toro, William A Gahl, May Christine V Malicdan, Cynthia J Tifft, Erika M Zink, Kent J Bloodsworth, Kelly G Stratton, Undiagnosed Diseases Network, David M Koeller, Thomas O Metz, Philip Washbourne, and Monte Westerfield
- Subjects
Central Nervous System ,Macroglial Cells ,Life Cycles ,Cancer Research ,Embryo, Nonmammalian ,Organogenesis ,DNA Mutational Analysis ,QH426-470 ,Nervous System ,Myelin ,Larvae ,Nerve Fibers ,0302 clinical medicine ,Animal Cells ,Medicine and Health Sciences ,Gray Matter ,Child ,Frameshift Mutation ,Zebrafish ,Myelin Sheath ,Genetics (clinical) ,Neurons ,0303 health sciences ,biology ,Nerves ,Gene Expression Regulation, Developmental ,Eukaryota ,Animal Models ,Magnetic Resonance Imaging ,Sciatic Nerve ,White Matter ,Cell biology ,Oligodendroglia ,medicine.anatomical_structure ,Experimental Organism Systems ,Spinal Cord ,Somites ,Osteichthyes ,Vertebrates ,Female ,Cellular Types ,Anatomy ,Neuroglia ,Research Article ,Neurogenesis ,Schwann cell ,Glial Cells ,Research and Analysis Methods ,Perineurial Cell ,03 medical and health sciences ,Model Organisms ,Exome Sequencing ,medicine ,Genetics ,Humans ,Animals ,Brachial Plexus ,Cerebral hypomyelination ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Tumor Suppressor Proteins ,Organisms ,Correction ,Biology and Life Sciences ,Cell Biology ,Zebrafish Proteins ,biology.organism_classification ,Axons ,Oligodendrocyte ,Myelin basic protein ,Disease Models, Animal ,Hereditary Central Nervous System Demyelinating Diseases ,Neuroanatomy ,Fish ,Cellular Neuroscience ,Animal Studies ,biology.protein ,Schwann Cells ,Schwann cell differentiation ,Organism Development ,030217 neurology & neurosurgery ,Developmental Biology ,Neuroscience - Abstract
Hypomyelination, a neurological condition characterized by decreased production of myelin sheets by glial cells, often has no known etiology. Elucidating the genetic causes of hypomyelination provides a better understanding of myelination, as well as means to diagnose, council, and treat patients. Here, we present evidence that YIPPEE LIKE 3 (YPEL3), a gene whose developmental role was previously unknown, is required for central and peripheral glial cell development. We identified a child with a constellation of clinical features including cerebral hypomyelination, abnormal peripheral nerve conduction, hypotonia, areflexia, and hypertrophic peripheral nerves. Exome and genome sequencing revealed a de novo mutation that creates a frameshift in the open reading frame of YPEL3, leading to an early stop codon. We used zebrafish as a model system to validate that YPEL3 mutations are causative of neuropathy. We found that ypel3 is expressed in the zebrafish central and peripheral nervous system. Using CRISPR/Cas9 technology, we created zebrafish mutants carrying a genomic lesion similar to that of the patient. Our analysis revealed that Ypel3 is required for development of oligodendrocyte precursor cells, timely exit of the perineurial glial precursors from the central nervous system (CNS), formation of the perineurium, and Schwann cell maturation. Consistent with these observations, zebrafish ypel3 mutants have metabolomic signatures characteristic of oligodendrocyte and Schwann cell differentiation defects, show decreased levels of Myelin basic protein in the central and peripheral nervous system, and develop defasciculated peripheral nerves. Locomotion defects were observed in adult zebrafish ypel3 mutants. These studies demonstrate that Ypel3 is a novel gene required for perineurial cell development and glial myelination., Author summary The study of congenital rare diseases allows the identification of new gene variants involved in development. Genetic and sequence analysis of a patient with a novel complex phenotype including hypomyelination, enlarged peripheral nerves, and motor defects implicated a de novo mutation in the YPEL3 gene as potentially causative. YPEL3 had not previously been associated with disease. Using CRISPR technology, we created a zebrafish model carrying a DNA lesion similar to that of the affected patient. Homozygous mutant embryos display weak and variable peripheral nerve phenotypes and are viable. Because ypel3 transcripts are present from fertilization, we generated maternal zygotic mutants. Analysis of these mutants revealed hypomyelination, defective axonal wrapping, and swimming defects. Time-lapse video lineage analysis showed that ypel3 is required for proper development of oligodendrocytes, Schwann cells, and perineurial cells. These results identify YPEL3 as a new regulator of glial cell development and support the conclusion that the de novo YPEL3 mutation is responsible for the patient’s disease.
- Published
- 2020