PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy

Abstract

Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.

EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons

“…This is particularly pronounced in the case of AKT2 loss of function (26) and in SHORT syndrome (29,31), but a generalised paucity of adipose tissue is also commonly described in the more severe insulin receptoropathies. The potential importance of this for the IR subphenotype that is clinically expressed is discussed below.…”

“…The latest form of severe IR established to be caused by mutation of an insulin signalling gene is seen in the context of SHORT syndrome, denoted by short stature, joint hyperextensibility and hernias, ocular depression, Rieger anomaly and teething delay. Although not part of the acronym, severe IR has been shown to be common in this disorder, and in 2012, the underlying cause was established to be mutations in the PIK3R1 gene (29,30,31). PIK3R1 encodes three of the regulatory subunits of type 1A PI3K, which are critical for the coupling of insulin binding to its receptor to activation of AKT2 and other downstream signalling molecules (12).…”

PI3-kinase mutation linked to insulin and growth factor resistance in vivo

“…The most common mutation in the affected individuals is the Arg649Trp missense mutation; we have demonstrated that this mutation markedly attenuates the insulin-dependent activation of the PI3K pathway in vitro (11). Other missense mutations (Glu489Lys, Arg631Gln), as well as a deletion (Ile539del), truncation (Tyr657*), and frame-shift insertions (Asn636Thrfs*18, Asp643Aspfs*8, Arg649Profs*5), have also been described (3,7,8,15). In the present study, we have generated knockin mice that are heterozygous for the most common mutation (Arg649Trp) observed in patients with SHORT syndrome to define the role of this mutation on the The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors.…”

“…Subsequent evaluation of additional patients revealed other prominent features, including partial lipodystrophy, with a selective reduction in subcutaneous adipose tissue in the face, flank, and buttocks, as well as marked insulin resistance (7,8). Recently, we and others have shown that the SHORT syndrome is associated with mutations in the Pik3r1 gene that encodes p85α (11)(12)(13)(14)(15). Most mutations cluster in the region encoding the C-terminal SH2 domain of p85α that is essential for binding of PI3K to tyrosine phosphorylated proteins, such as insulin receptor (IR) substrate-1 (IRS-1) and many growth factor receptors (11,12,14,15).…”

“…Recently, we and others have shown that the SHORT syndrome is associated with mutations in the Pik3r1 gene that encodes p85α (11)(12)(13)(14)(15). Most mutations cluster in the region encoding the C-terminal SH2 domain of p85α that is essential for binding of PI3K to tyrosine phosphorylated proteins, such as insulin receptor (IR) substrate-1 (IRS-1) and many growth factor receptors (11,12,14,15). The most common mutation in the affected individuals is the Arg649Trp missense mutation; we have demonstrated that this mutation markedly attenuates the insulin-dependent activation of the PI3K pathway in vitro (11).…”