A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia.
We describe a child with onset of command auditory hallucinations and behavioral regression at 6 yr of age in the context of longer standing selective mutism, aggression, and mild motor delays. His genetic evaluation included chromosomal microarray analysis and whole-exome sequencing. Sequencing revealed a previously unreported heterozygous de novo mutation c.385G>A in ATP1A3, predicted to result in a p.V129M amino acid change. This gene codes for a neuron-specific isoform of the catalytic α-subunit of the ATP-dependent transmembrane sodium-potassium pump. Heterozygous mutations in this gene have been reported as causing both sporadic and inherited forms of alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism. We discuss the literature on phenotypes associated with known variants in ATP1A3, examine past functional studies of the role of ATP1A3 in neuronal function, and describe a novel clinical presentation associated with mutation of this gene.
Division of Immunology, Harvard Medical School, Boston, Massachusetts 02115, USA;; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
Niklas
N
Smedemark-Margulies
The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA;
Catherine A
CA
Brownstein
Developmental Neuropsychiatry Research Program, Department of Psychiatry, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
Sigella
S
Vargas
Developmental Neuropsychiatry Research Program, Department of Psychiatry, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
Sahil K
SK
Tembulkar
The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
Meghan C
MC
Towne
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China;
Jiahai
J
Shi
The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
Elisa
E
Gonzalez-Cuevas
Developmental Neuropsychiatry Research Program, Department of Psychiatry, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
Kevin X
KX
Liu
Department of Genetics, Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut 06511, USA;
Kaya
K
Bilguvar
Translational Neuroscience Center, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA;; Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
Robin J
RJ
Kleiman
Translational Neuroscience Center, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA;; Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
Min-Joon
MJ
Han
Division of Pediatric Neurology, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts 02118, USA;
Alcy
A
Torres
The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
Gerard T
GT
Berry
The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA;
Timothy W
TW
Yu
The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA;
Alan H
AH
Beggs
The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA;; Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
Pankaj B
PB
Agrawal
Developmental Neuropsychiatry Research Program, Department of Psychiatry, Boston Children's Hospital, Boston, Massachusetts 02115, USA;; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA.
Joseph
J
Gonzalez-Heydrich
psychotic mentation