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Identification and characterisation of a novel constitutional PIK3CA mutation in a child lacking the typical segmental overgrowth of "PIK3CA-Related Overgrowth Spectrum" (PROS)
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posted on 2023-06-08, 23:37 authored by Nataliya Di Donato, Andreas Rump, Ghayda M Mirzaa, Diana AlcantaraDiana Alcantara, Antony OliverAntony Oliver, Evelin Schrock, William B Dobyns, Mark O'DriscollMark O'DriscollActivating somatic PIK3CA mutations underlie a growing heterogeneous spectrum of segmental overgrowth disorders. We report the identification and evaluation of a novel de novo constitutional PIK3CA mutation (NM_006218.2:c.335T>A, p.Ile112Asn) in a child with congenital megalencephaly and macrosomia. Functional characterization of patient cells using a variety of endpoints demonstrates increased Phosphatidylinositol-3-kinase (PI3K) activity. The mutation lies in a linker region adjacent to the p85 (PIK3R2) binding domain of the p110a (PIK3CA) catalytic subunit of PI3K. We show that altered stoichiometry within the p85-p110 complex likely underlies the hyperactive PI3K-AKT-mTOR signaling in this instance. Our findings expand upon the recently proposed "PIK3CA-Related Overgrowth Spectrum" (PROS) associated with PIKC3A-mutations and PI3K hyper-activation, adding constitutional PIK3CA mutations as an underlying cause of megalencephaly and macrosomia in newborns. This article is protected by copyright. All rights reserved.
History
Publication status
- Published
Journal
Human MutationISSN
1059-7794Publisher
John Wiley & SonsExternal DOI
Issue
3Volume
37Page range
242-245Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2015-12-03Usage metrics
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