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Background   ATP1A3  encodes the α3 subunit of the Na + /K +  ATPase, a fundamental ion-transporting enzyme. Primarily expressed in neurons,  ATP1A3  is mutated in several autosomal dominant neurological diseases. To our knowledge, damaging recessive genotypes in  ATP1A3  have never been associated with any human disease.  Atp1a3  deficiency in zebrafish results in hydrocephalus; however, no known association exists between  ATP1A3  and human congenital hydrocephalus (CH).    Methods  We utilized whole-exome sequencing (WES), bioinformatics, and computational modeling to identify and characterize novel  ATP1A3  mutations in a patient with CH. We performed immunohistochemical studies using mouse embryonic brain tissues to characterize  Atp1a3  expression during brain development.    Results  We identified two germline mutations in  ATP1A3  (p. Arg19Cys and p.Arg463Cys), each of which was inherited from one of the patient’s unaffected parents, in a single patient with severe obstructive CH due to aqueductal stenosis, along with open schizencephaly, type 1 Chiari malformation, and dysgenesis of the corpus callosum. Both mutations are predicted to be highly deleterious and impair protein stability. Immunohistochemical studies demonstrate robust  Atp1a3  expression in neural stem cells (NSCs), differentiated neurons, and choroid plexus of the mouse embryonic brain.    Conclusion  These data provide the first evidence of a recessive human phenotype associated with mutations in  ATP1A3 , and implicate impaired Na + /K +  ATPase function in the pathogenesis of CH.

Recessive Inheritance of Congenital Hydrocephalus With Other Structural Brain Abnormalities Caused by Compound Heterozygous Mutations in ATP1A3