The Endocannabinoid System: A Potential Therapeutic Target for Coagulopathies.

Abnormal blood coagulation or coagulopathy is a common manifestation of many pathological conditions. It occurs when there is an imbalance between the activities of the coagulation system and the fibrinolytic system, leading to excessive or impaired intravascular blood clot formation, which can disturb blood flow causing ischemia or hemorrhage in the affected tissues. A growing body of evidence has demonstrated blood coagulation abnormalities in association with cannabinoid use, suggesting the involvement of the endogenous cannabinoid system (ECS) in modulating blood coagulation. However, the evidence in the literature has been controversial on whether cannabinoids promote or inhibit blood coagulation. The ECS has been extensively studied in recent years for its potential as a therapeutic target for many diseases. This review provides a brief introduction to the ECS and discusses the reported anticoagulatory and procoagulatory effects of various cannabinoids, highlighting some possible mechanisms that might underlie the observed effects. Understanding the coagulatory effects of cannabinoids and the interaction between the coagulation system and the ECS is vital for developing novel therapeutics for coagulopathies.

A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation.

We report two unrelated families with multigenerational nonsyndromic intellectual disability (ID) segregating with a recurrent de novo missense variant (c.1543C>T:p.Leu515Phe) in the alkali cation/proton exchanger gene SLC9A7 (also commonly referred to as NHE7). SLC9A7 is located on human X chromosome at Xp11.3 and has not yet been associated with a human phenotype. The gene is widely transcribed, but especially abundant in brain, skeletal muscle and various secretory tissues. Within cells, SLC9A7 resides in the Golgi apparatus, with prominent enrichment in the trans-Golgi network (TGN) and post-Golgi vesicles. In transfected Chinese hamster ovary AP-1 cells, the Leu515Phe mutant protein was correctly targeted to the TGN/post-Golgi vesicles, but its N-linked oligosaccharide maturation as well as that of a co-transfected secretory membrane glycoprotein, vesicular stomatitis virus G (VSVG) glycoprotein, was reduced compared to cells co-expressing SLC9A7 wild-type and VSVG. This correlated with alkalinization of the TGN/post-Golgi compartments, suggestive of a gain-of-function. Membrane trafficking of glycosylation-deficient Leu515Phe and co-transfected VSVG to the cell surface, however, was relatively unaffected. Mass spectrometry analysis of patient sera also revealed an abnormal N-glycosylation profile for transferrin, a clinical diagnostic marker for congenital disorders of glycosylation. These data implicate a crucial role for SLC9A7 in the regulation of TGN/post-Golgi pH homeostasis and glycosylation of exported cargo, which may underlie the cellular pathophysiology and neurodevelopmental deficits associated with this particular nonsyndromic form of X-linked ID.