A potential gain-of-function variant of SLC9A6 leads to endosomal alkalinization and neuronal atrophy associated with Christianson Syndrome

Exosomes: Revisiting their role as “garbage bags”

“…Various studies have recently suggested that there is cross‐regulation between the exosomal pathway and lysosomal degradation. Lysosome inhibitors such as chloroquine or bafilomycin A1 have been shown to increase exosome release. Moreover, it was demonstrated that Atg5 dissociates V 1 V 0 ‐ATPase in endosomes, in turn decreasing endosomal acidification and promoting exosome secretion .…”

“…Cone-shaped lipids are important for curving and bending membrane 39 while also being involved in membrane fusion, 40 and thus their local production could facilitate two critical exosome biogenesis steps. Lysosome inhibitors such as chloroquine 42 or bafilomycin A1 41,43 have been shown to increase exosome release. Moreover, it was demonstrated that Atg5 dissociates V 1 V 0 -ATPase in endosomes, in turn decreasing endosomal acidification and promoting exosome secretion.…”

Assorted dysfunctions of endosomal alkali cation/proton exchanger SLC9A6 variants linked to Christianson syndrome

“…Of the aforementioned six mutations, two (L188P and G383D) were localized within the transmembrane ion translocation domain which afforded an opportunity to assess the theoretically structural and functional implications of these substitutions by structure homology modelling. In this regard, we previously described a putative structural model of the human NHE6 N-terminal transmembrane region (encompassing residues 74-540) in its monomeric state using the spatial atomic coordinates of the outward-facing conformation of the Thermus thermophilus Na + /H + antiporter NapA (57,62). However, mammalian NHEs, like their bacterial homologs, normally form homodimers (63).…”

“…To biochemically assess the ability of the NHE6 variants to traffic to the plasma membrane, plasmalemmal proteins were extracted using a cell surface biotinylation procedure and analyzed by Western blotting. We previously showed that ~5% of the total cellular pool of NHE6 is located at the cell surface of transfected AP-1 cells (57). Due to the low levels of expression of some of the NHE6 variants, we loaded varying amounts of protein in each lane (as indicated) so that their signal intensities would be comparable and easily visualized within a single X-ray film exposure of the immunoblots.…”

“…More than 80 genetic variants of NHE6 have been identified thus far (also see ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and DECIPHER (https://decipher.sanger.ac.uk/)), many of which are frameshift and nonsense mutations or mRNA splicing defects in the ion translocation domain (amino acids that are predicted to result in total loss of NHE6 protein. However, the consequences on endosomal and cellular function of other CSlinked NHE6 mutations that may not lead to a complete loss of protein expression or function have been less well documented (53,(55)(56)(57). These include missense substitutions, small inframe deletions, or nonsense mutations in the Cterminal regulatory domain that may generate protein products with altered functional properties (i.e., dominant-negative or constitutively-active) which, alongside other genetic factors, could contribute to reported variations in disease severity of CS patients (15).…”