Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly.

Giant ankyrin-G (gAnkG) coordinates assembly of axon initial segments (AISs), which are sites of action potential generation located in proximal axons of most vertebrate neurons. Here, we identify a mechanism required for normal neural development in humans that ensures ordered recruitment of gAnkG and ß4-spectrin to the AIS. We identified 3 human neurodevelopmental missense mutations located in the neurospecific domain of gAnkG that prevent recruitment of ß4-spectrin, resulting in a lower density and more elongated pattern for gAnkG and its partners than in the mature AIS. We found that these mutations inhibit transition of gAnkG from a closed configuration with close apposition of N- and C-terminal domains to an extended state that is required for binding and recruitment of ß4-spectrin, and normally occurs early in development of the AIS. We further found that the neurospecific domain is highly phosphorylated in mouse brain, and that phosphorylation at 2 sites (S1982 and S2619) is required for the conformational change and for recruitment of ß4-spectrin. Together, these findings resolve a discrete intermediate stage in formation of the AIS that is regulated through phosphorylation of the neurospecific domain of gAnkG.

An alternative coverage for split thickness skin graft donor site wounds.

Diabetic foot and ankle soft tissue reconstruction poses a difficult challenge to the treating surgeon, especially in cases associated with previous infection or amputation. Maintenance of a functional, plantigrade limb is important with regard to prevention of persistent or recurrent cutaneous compromise following diabetic limb salvage. Wound coverage by means of application of a split thickness skin graft (STSG) is a useful technique; however, donor site wounds require care during the early postoperative period, and can pose a challenge to wound healing in and of themselves. In this article, we describe a technique of management of STSG donor site wounds that we have found to be useful and well tolerated by our patients.