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.

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1997 saw the identification of a novel set of proteins within the tumor necrosis factor (TNF)/TNF receptor families that are required for the control of bone remodeling. Therefore, these receptors, receptor activator of nuclear factor kappa B (RANK), osteoprotegerin (OPG) and their ligand RANK ligand (RANKL) became the critical molecular triad controlling osteoclastogenesis and pathophysiologic bone remodeling. However, the establishment of the corresponding knock-out and transgenic mice revealed unexpected results, most particularly, the involvement of these factors in the vascular system and immunity. Thus, the OPG/RANK/RANKL molecular triad appears to be associated with vascular calcifications and plays a pivotal function in the development of the immune system through dendritic cells. OPG/RANK/RANKL thus constitute a molecular bridge spanning bone metabolism, vascular biology and immunity. This review summarizes recent knowledge of OPG/RANK/RANKL interactions and activities as well as the current evidence for their participation in osteoimmunology and vascular diseases. In fine, the targeting of the OPG/RANK/RANKL axis as novel therapeutic approaches will be discussed.