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PLoS Genet ; 16(6): e1008841, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32544203

RESUMEN

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.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Vaina de Mielina/patología , Neurogénesis/genética , Proteínas Supresoras de Tumor/genética , Animales , Plexo Braquial/diagnóstico por imagen , Niño , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Embrión no Mamífero , Femenino , Mutación del Sistema de Lectura , Sustancia Gris/diagnóstico por imagen , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico por imagen , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/patología , Humanos , Imagen por Resonancia Magnética , Neuroglía/patología , Oligodendroglía , Nervio Ciático/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Secuenciación del Exoma , Pez Cebra , Proteínas de Pez Cebra/genética
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