期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 101, 期 4, 页码 516-524出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2017.08.013
关键词
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资金
- Lennox-Gaustaut Syndrome Foundation
- American Epilepsy Society
- NIH National Institute of Neurological Disorders and Stroke [RO1 NS069605, U01NS077303, U01NS053998]
- Health Research Council of New Zealand
- Cure Kids New Zealand
- Australian National Health and Medical Research Council [APP1054618, APP1102971]
- Victorian State Government Operational Infrastructure Support
- Australian Government NHMRC IRIISS funding
- Janssen
- Gilead
- Biogen
- AstraZeneca
- UCB
- Eisai
- Athena Diagnostics
- GlaxoSmithKline
- Nutricia
- Transgenomics
- Biocodex
Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium-and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 x 10(-8)) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory epilepsy and further support the emerging role for synaptic dysregulation in epilepsy.
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