Donato, Nataliya Di, Rump, Andreas, Mirzaa, Ghayda M, Alcantara, Diana, Oliver, Antony, Schrock, Evelin, Dobyns, William B and O'Driscoll, Mark (2015) Identification and characterisation of a novel constitutional PIK3CA mutation in a child lacking the typical segmental overgrowth of "PIK3CA-Related Overgrowth Spectrum" (PROS). Human Mutation, 37 (3). pp. 242-245. ISSN 1059-7794

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Abstract

Activating 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 p110α (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.

Item Type:	Article
Schools and Departments:	School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects:	Q Science
Depositing User:	Antony Oliver
Date Deposited:	03 Dec 2015 11:57
Last Modified:	26 Sep 2016 14:04
URI:	http://sro.sussex.ac.uk/id/eprint/58600

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