학술논문
De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures.
Document Type
Article
Author
Myers, Candace T.; Stong, Nicholas; Mountier, Emily I.; Helbig, Katherine L.; Freytag, Saskia; Sullivan, Joseph E.; Ben Zeev, Bruria; Nissenkorn, Andreea; Tzadok, Michal; Heimer, Gali; Shinde, Deepali N.; Rezazadeh, Arezoo; Regan, Brigid M.; Oliver, Karen L.; Ernst, Michelle E.; Lippa, Natalie C.; Mulhern, Maureen S.; Ren, Zhong; Poduri, Annapurna; Andrade, Danielle M.
Source
Subject
*GENETIC mutation
*NEURODEGENERATION
*GENETICS of epilepsy
*CALCINEURIN
*NUCLEOTIDE sequencing
*DEVELOPMENTAL delay
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Language
ISSN
0002-9297
Abstract
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 × 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. [ABSTRACT FROM AUTHOR]