ATP1A3 Mutation in Adult Rapid-Onset Ataxia

Abstract

A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient’s ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative.

In Vivo Modelling of ATP1A3 G316S-Induced Ataxia in C. elegans Using CRISPR/Cas9-Mediated Homologous Recombination Reveals Dominant Loss of Function Defects

“…In HEK293 cells, when the endogenous pump is inhibited by ouabain, exogenous overexpression of the mutant pump is not sufficient for complete viability of the cells. These results show that the mutation causes a loss of function [2]. Behavioral and genetic results presented here are consistent with the G304S mutation in C .…”

“…we conclude that the G316S mutation in ATP1A3 likely causes the patient’s syndrome. In addition to this, as explained by Sweadner et al ., the UBQLN4 mutation that the patient carries might aggravate the symptoms[2]. Modelling this rare disease provides a strategy for modelling other rare diseases and may contribute to developing treatments for these devastating disorders.…”

“…The mutation is predicted to impact protein function and potentially cause patient symptoms. Recently, the G316S mutation was shown to reduce pump activity when ATP1A3 was overexpressed in vitro [2]. …”

Progressive Brain Atrophy in Alternating Hemiplegia of Childhood

“…From our observations, cerebellar Purkinje and granule cell layers, pyramidal cells in the frontal cortex, and the hippocampus might be targets for several ATP1A3 mutations in some patients with AHC. A special RDP patient who displayed cerebellar atrophy with ATP1A3 and another gene mutation was recently reported . When patients with ATP1A3 mutations have cerebral or cerebellar atrophy, there could be any other gene mutations, some other epigenetic factors, or exogenous factors such as hypoxia.…”

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

“…Although the three syndromes were originally identified as phenotypically distinct, it has become clear that many patients do not strictly fall into one category or the other, but may have symptoms that fall on a continuous spectrum as well as unique symptoms for individual mutations (Rosewich et al, 2014; Paciorkowski et al, 2015; Sweney et al, 2015; Kanemasa et al, 2016; Liu et al, 2016; Smedemark-Margulies et al, 2016; Sweadner et al, 2016). …”