PIK3R1 mutations in individuals with insulin resistance or growth retardation: Case series and in silico functional analysis.

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 binding of p85α to phosphopeptide and thereby impairing insulin signaling. One case uniquely manifested diabetes without insulin resistance, emphasizing the need for further study of the clinical variability of SHORT syndrome, especially with regard to its associated diabetes.