Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal
Alex R Paciorkowski1, Sharon S McDaniel, Laura A Jansen
1Departments 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.
Insights
Novel mutations in the ATP1A3 gene are linked to severe neurological disorders in children, including early-onset epilepsy and developmental issues. These findings expand the understanding of ATP1A3-related disorders and their impact on brain function.
Area of Science:
- Genetics and Neurology
- Molecular Biology
- Neuroscience
Background:
- Mutations in ATP1A3 are known to cause rapid onset dystonia-parkinsonism and alternating hemiplegia of childhood.
- ATP1A3 encodes a subunit of the sodium-potassium pump (Na,K-ATPase), crucial for neuronal function.
Purpose of the Study:
- To identify and characterize novel mutations in ATP1A3 associated with severe early-life neurological conditions.
- To investigate the functional consequences of these mutations on ATP1A3 protein activity and its role in brain pathology.
Main Methods:
- Next-generation sequencing was used to identify mutations in affected children.
- Clinical data were retrospectively collected.
- In vitro biochemical assays and postmortem neuropathologic studies were performed to assess mutation effects.
Main Results:
- Two novel heterozygous mutations (p.Gly358Val and p.Ile363Asn) in ATP1A3 were identified in children with severe epilepsy and developmental disabilities.
- These mutations significantly reduced Na,K-ATPase activity in vitro.
- ATP1A3 protein was found to be prominently associated with cortical interneurons, suggesting a role in their dysfunction.
Conclusions:
- The identified ATP1A3 mutations cause severe phenotypes within the ATP1A3-related disorder spectrum.
- These phenotypes include catastrophic early-life epilepsy, episodic apnea, and postnatal microcephaly.
- The findings highlight the critical role of ATP1A3 in early neurodevelopment and neuronal function.
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.
More Related Videos
08:04Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons
Published on: June 6, 2025
06:41In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Related Concept Videos
01:48ATP Synthase: Mechanism
01:18ATP Synthase: Structure