PIK3R1 mutations in individuals with insulin resistance or growth retardation: Case series and in silico functional analysis
Abstract
AIMS/INTRODUCTION: Phosphatidylinositol 3-kinase (PI3K) plays a key role in insulin signaling, and mutations in PIK3R1, which encodes a regulatory subunit (p85α) of this enzyme, are responsible for SHORT syndrome, which is associated with insulin-resistant diabetes. We here describe four Japanese individuals from three families with SHORT syndrome who harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins. MATERIALS AND METHODS: Gene sequencing was performed to identify PIK3R1 mutations. 3D structural analysis of wild-type and mutant p85α proteins was performed by homology modeling, and structural optimization and molecular dynamics simulations confirmed stable trajectories. Docking simulations of p85α with a phosphopeptide were also conducted. RESULTS: We identified two families with a common mutation (c.1945C>T, p.R649W) and one family with a previously unidentified mutation (c.1957A>T, p.K653*) of PIK3R1. In silico modeling revealed that both mutations impaired binding of p85α to phosphopeptide, with K653* resulting in the loss of amino acids that contribute to such binding. Docking simulations showed a significant loss of docking energy for the R649W mutant compared with the wild-type protein (P = 0.00329). CONCLUSIONS: The four cases of SHORT syndrome were associated with early-onset diabetes and intrauterine growth retardation, with the identified mutations likely disrupting the…
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Evidence Hub reads this as a case series, done in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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