Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly
Corresponding Author
Alex R. Paciorkowski
Departments of Neurology, Pediatrics, and Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, U.S.A
Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York, U.S.A
Address correspondence to Alex R. Paciorkowski, Child Neurology, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, U.S.A. E-mail: [email protected]Search for more papers by this authorSharon S. McDaniel
Department of Pediatrics, Kaiser Permanente, San Francisco, California, U.S.A
Search for more papers by this authorLaura A. Jansen
Department of Neurology, University of Virginia, Charlottesville, Virginia, U.S.A
Search for more papers by this authorHannah Tully
Department of Neurology, University of Washington, Seattle, Washington, U.S.A
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, U.S.A
Search for more papers by this authorEmily Tuttle
Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York, U.S.A
Search for more papers by this authorDalia H. Ghoneim
Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York, U.S.A
Search for more papers by this authorSrinivasan Tupal
Department of Neurology, University of Virginia, Charlottesville, Virginia, U.S.A
Search for more papers by this authorSonya A. Gunter
Department of Neurology, University of Virginia, Charlottesville, Virginia, U.S.A
Search for more papers by this authorValeria Vasta
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, U.S.A
Search for more papers by this authorQing Zhang
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, U.S.A
Search for more papers by this authorThao Tran
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, U.S.A
Search for more papers by this authorYi B. Liu
Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, U.S.A
Search for more papers by this authorLaurie J. Ozelius
Departments of Genetics, Genomic Sciences, and Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, U.S.A
Search for more papers by this authorAllison Brashear
Department of Neurology, Wake Forest School of Medicine, Winston Salem, North Carolina, U.S.A
Search for more papers by this authorKathleen J. Sweadner
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A
Search for more papers by this authorWilliam B. Dobyns
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, U.S.A
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, U.S.A
Search for more papers by this authorSihoun Hahn
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, U.S.A
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, U.S.A
Search for more papers by this authorCorresponding Author
Alex R. Paciorkowski
Departments of Neurology, Pediatrics, and Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, U.S.A
Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York, U.S.A
Address correspondence to Alex R. Paciorkowski, Child Neurology, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, U.S.A. E-mail: [email protected]Search for more papers by this authorSharon S. McDaniel
Department of Pediatrics, Kaiser Permanente, San Francisco, California, U.S.A
Search for more papers by this authorLaura A. Jansen
Department of Neurology, University of Virginia, Charlottesville, Virginia, U.S.A
Search for more papers by this authorHannah Tully
Department of Neurology, University of Washington, Seattle, Washington, U.S.A
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, U.S.A
Search for more papers by this authorEmily Tuttle
Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York, U.S.A
Search for more papers by this authorDalia H. Ghoneim
Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York, U.S.A
Search for more papers by this authorSrinivasan Tupal
Department of Neurology, University of Virginia, Charlottesville, Virginia, U.S.A
Search for more papers by this authorSonya A. Gunter
Department of Neurology, University of Virginia, Charlottesville, Virginia, U.S.A
Search for more papers by this authorValeria Vasta
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, U.S.A
Search for more papers by this authorQing Zhang
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, U.S.A
Search for more papers by this authorThao Tran
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, U.S.A
Search for more papers by this authorYi B. Liu
Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, U.S.A
Search for more papers by this authorLaurie J. Ozelius
Departments of Genetics, Genomic Sciences, and Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, U.S.A
Search for more papers by this authorAllison Brashear
Department of Neurology, Wake Forest School of Medicine, Winston Salem, North Carolina, U.S.A
Search for more papers by this authorKathleen J. Sweadner
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A
Search for more papers by this authorWilliam B. Dobyns
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, U.S.A
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, U.S.A
Search for more papers by this authorSihoun Hahn
Center for Developmental Therapeutics, Seattle Children's Research Institute, Seattle, Washington, U.S.A
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, U.S.A
Search for more papers by this authorSummary
Objective
Mutations of ATP1A3 have been associated with rapid onset dystonia-parkinsonism and more recently with alternating hemiplegia of childhood. Here we report one child with catastrophic early life epilepsy and shortened survival, and another with epilepsy, episodic prolonged apnea, postnatal microcephaly, and severe developmental disability. Novel heterozygous mutations (p.Gly358Val and p.Ile363Asn) were identified in ATP1A3 in these children.
Methods
Subjects underwent next-generation sequencing under a research protocol. Clinical data were collected retrospectively. The biochemical effects of the mutations on ATP1A3 protein function were investigated. Postmortem neuropathologic specimens from control and affected subjects were studied.
Results
The mutations localized to the P domain of the Na,K-ATPase α3 protein, and resulted in significant reduction of Na,K-ATPase activity in vitro. We demonstrate in both control human brain tissue and that from the subject with the p.Gly358Val mutation that ATP1A3 immunofluorescence is prominently associated with interneurons in the cortex, which may provide some insight into the pathogenesis of the disease.
Significance
The findings indicate these mutations cause severe phenotypes of ATP1A3-related disorder spectrum that include catastrophic early life epilepsy, episodic apnea, and postnatal microcephaly.
Supporting Information
| Filename | Description |
|---|---|
| epi12914-sup-0001-FigS1.tifimage/tif, 6.8 MB | Figure S1. Neuropathologic findings in ATP1A3 Gly358Val brain. |
| epi12914-sup-0002-TableS1.docWord document, 27.5 KB | Table S1. Massively parallel sequencing metrics. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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