yippee like 3 (ypel3) is a novel gene required for myelinating and perineurial glia development

Blanco-Sánchez, B., Clément, A., Stednitz, S.J., Kyle, J., Peirce, J.L., McFadden, M., Wegner, J., Phillips, J.B., Macnamara, E., Huang, Y., Adams, D.R., Toro, C., Gahl, W.A., Malicdan, M.C.V., Tifft, C.J., Zink, E.M., Bloodsworth, K.J., Stratton, K.G., Undiagnosed Diseases Network, Koeller, D.M., Metz, T.O., Washbourne, P., Westerfield, M.
PLoS Genetics   16: e1008841 (Journal)
Registered Authors
Blanco, Bernardo, Clément, Aurélie, McFadden, Marcie, Peirce, Judy, Phillips, Jennifer, Washbourne, Philip, Wegner, Jeremy, Westerfield, Monte
MeSH Terms
  • Animals
  • Brachial Plexus/diagnostic imaging
  • Child
  • DNA Mutational Analysis
  • Disease Models, Animal
  • Embryo, Nonmammalian
  • Female
  • Frameshift Mutation
  • Gene Expression Regulation, Developmental*
  • Gray Matter/diagnostic imaging
  • Hereditary Central Nervous System Demyelinating Diseases/diagnostic imaging
  • Hereditary Central Nervous System Demyelinating Diseases/genetics*
  • Hereditary Central Nervous System Demyelinating Diseases/pathology
  • Humans
  • Magnetic Resonance Imaging
  • Myelin Sheath/pathology*
  • Neurogenesis/genetics*
  • Neuroglia/pathology
  • Oligodendroglia
  • Sciatic Nerve/diagnostic imaging
  • Tumor Suppressor Proteins/genetics*
  • White Matter/diagnostic imaging
  • Whole Exome Sequencing
  • Zebrafish
  • Zebrafish Proteins/genetics
32544203 Full text @ PLoS Genet.
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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes
Correction: Corrects Article: