PIK3R1 mutations in SHORT syndrome

Abstract

SHORT syndrome (OMIM 269880) is a rare autosomal-dominant disorder characterized by short stature, hyperextensibility of joints, hernias, ocular depression, ophthalmic anomalies (Rieger anomaly, posterior embryotoxon, glaucoma), teething delay, partial lipodystrophy, insulin resistance and facial dysmorphic signs. Heterozygous mutations in PIK3R1 were recently identified in 14 families with SHORT syndrome. Eight of these families had a recurrent missense mutation (c.1945C>T; p.Arg649Trp). We report on two unrelated patients with typical clinical features of SHORT syndrome and additional problems such as pulmonary stenosis and ectopic kidney. Analysis of PIK3R1 revealed the mutation c.1945C>T; p.Arg649Trp de novo in both patients. These two patients not only provide additional evidence that PIK3R1 mutations cause SHORT syndrome, but also broaden the clinical spectrum of this syndrome and further confirm that the amino acid exchange c.1945C>T; p.Arg649Trp is a hotspot mutation in this gene.

Combined GWAS and ‘guilt by association’-based prioritization analysis identifies functional candidate genes for body size in sheep

“…The PIK3R5 , RPL26 , PSMA8 and APAF1 genes fall within this category since they are not associated with relevant mammalian phenotypes but they were highly prioritized either overall or within the respective SNP. PIK3R5, is a regulatory subunit of the class I phosphatidylinositol 3-kinase (PI3K) gamma complex and it has been shown that mutations in another PI3K regulatory gene subunit, PIK3R1 , are responsible for human short syndrome [37–39], which is characterized by a variety of symptoms including short stature. Moreover, the PI3K signaling pathway has been implicated in growth hormone and insulin resistance [40].…”

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

“…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).…”

Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind

“…Lymphoproliferation and autoimmunity have however also been reported [165,166••] but there were no overt signs of autoinflammation or allergy. Interestingly, other heterozygous PIK3R1 mutations have been reported in SHORT syndrome (OMIM#269880), without immunodeficiency, and these mutations appeared to decrease p-AKT levels in response to insulin [167-171]. Moreover, a homozygous LOF mutation of PIK3R1 had previously been shown to cause agammaglobulinemia and a selective blockade of B-cell development [172].…”