AUTHOR=Allocco August A. , Jin Sheng Chih , Duy Phan Q. , Furey Charuta G. , Zeng Xue , Dong Weilai , Nelson-Williams Carol , Karimy Jason K. , DeSpenza Tyrone , Hao Le T. , Reeves Benjamin , Haider Shozeb , Gunel Murat , Lifton Richard P. , Kahle Kristopher T. TITLE=Recessive Inheritance of Congenital Hydrocephalus With Other Structural Brain Abnormalities Caused by Compound Heterozygous Mutations in ATP1A3 JOURNAL=Frontiers in Cellular Neuroscience VOLUME=13 YEAR=2019 URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2019.00425 DOI=10.3389/fncel.2019.00425 ISSN=1662-5102 ABSTRACT=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.