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

August A Allocco,Le T Hao,Phan Q Duy,Charuta G Furey,Shozeb Haider,Tyrone Despenza,Murat Gunel,Benjamin Reeves,Jason K Karimy,Richard P Lifton,Kristopher T Kahle,Xue Zeng,Carol Nelson-Williams,Sheng Chih Jin,Weilai Dong

doi:10.3389/fncel.2019.00425

Abstract

BackgroundATP1A3 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).MethodsWe 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.ResultsWe 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.ConclusionThese 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.

Highlights

Congenital hydrocephalus (CH) is the most common reason for brain surgery in children and affects 1 in 1,000 newborns (Tully and Dobyns, 2014; Kahle et al, 2016)
Compound heterozygous mutations in ATP1A3 were identified in the affected individual
No homozygous loss-of-function mutations or homozygous damaging missense mutations in ATP1A3 have been reported in gnomAD

Summary

Introduction

Congenital hydrocephalus (CH) is the most common reason for brain surgery in children and affects 1 in 1,000 newborns (Tully and Dobyns, 2014; Kahle et al, 2016). There is a need to identify CH disease-causing genes, given that 40% of CH cases is estimated to have a genetic etiology (Haverkamp et al, 1999). Despite significant efforts to identify CH genes, including a recent whole-exome sequencing (WES) (Furey et al, 2018) study, the majority of CH cases remain idiopathic, underscoring the need for continued gene discovery. 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; no known association exists between ATP1A3 and human congenital hydrocephalus (CH)

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Results

Conclusion