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

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 thatYIPPEE 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 revealeda de novomutation that creates a frameshift in the open reading frame ofYPEL3, leading to an early stop codon. We used zebrafish as a model system to validate thatYPEL3mutations are causative of neuropathy. We found thatypel3is 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, zebrafishypel3mutants 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 zebrafishypel3mutants. 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 ade novomutation in theYPEL3gene as potentially causative.YPEL3had 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. Becauseypel3transcripts 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 thatypel3is 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 thede novo YPEL3mutation is responsible for the patient's disease.