title: 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.
authors.affiliation: Departments of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Sweadner
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, and Office of the Clinical Director, NHGRI, Bethesda, Maryland, United States of America.
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
authors.affiliation: Departments of Radiology and Biomedical Engineering, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Whitlow
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Beverly M
authors.initials: BM
authors.lastname: Snively
authors.affiliation: Department of Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Jared F
authors.initials: JF
authors.lastname: Cook
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston Massachusetts, United States of America.
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Ozelius
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, and Human Biochemical Genetics Section, Medical Genetics Branch, NHGRI, Bethesda, Maryland, United States of America.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Markello
authors.affiliation: Department of Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Allison
authors.initials: A
authors.lastname: Brashear
mesh_terms: D001259:Ataxia / Q000209:etiology / Q000235:genetics*; D001284:Atrophy / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002531:Cerebellum / Q000473:pathology; D004421:Dystonia / Q000235:genetics / Q000503:physiopathology; D020821:Dystonic Disorders / Q000209:etiology / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C488756:ATP1A3 protein, human; D002352:Carrier Proteins; C485668:GRIN1 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C421907:UBQLN4 protein, human; D000254:Sodium-Potassium-Exchanging ATPase