Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18‐2 mutations

Abstract

Mutations in STXBP2 do not only affect cytotoxic T lymphocytes but also cause changes in the intestinal and renal epithelium resulting in severe, osmotic diarrhea and renal proximal tubular dysfunction. These defects persist after successful treatment of hemophagocytic lymphohistocytosis by HSCT. Clinical manifestations in FHL5 patients despite successful HSCT may therefore be related to defective membrane trafficking in the gut and kidney.

Rab11a regulates Syntaxin 3 localization and microvillus assembly in enterocytes

“…We have previously observed in duodenal samples from microvillus inclusion disease patients that the brush borders in enterocytes of the proximal villus are intact (Knowles et al, 2014); loss of microvilli and development of microvillus inclusions only occur in the upper half of the villus. It is unclear from published findings whether patients with STX3 or Munc-18-2 mutations also show similar patterns of differential loss of brush border integrity during migration towards the villus tips (Stepensky et al, 2013;Wiegerinck et al, 2014). Nevertheless, it appears that loss of Rab11a and loss of functional MYO5B do not affect initial formation of the enterocyte brush border, but rather disrupt maintenance of polarity and brush border integrity in the enterocytes of the upper villus tip.…”

“…Loss of Rab11a also elicited redistribution and upregulation of Rab8a and Rab11b. Interestingly, the enterocytes of patients with STX3 mutations show many of the same characteristics as those in the Rab11a DIEC duodenum, including the presence of lateral microvilli (Stepensky et al, 2013;Wiegerinck et al, 2014). Previous investigations have noted the presence of STX3 on Rab11a-containing recycling vesicles (Lapierre et al, 2007).…”

“…Notably, expression of mutant STX3, without targeting sequence, disrupts the apical delivery of proteins in MDCK cells (Sharma et al, 2006). Recently, mutations in STX3 and STXBP2 (also known as Munc18-2) have been identified in neonates with severe neonatal diarrheal disease and alterations in enterocyte polarity associated with apical microvilli loss (Stepensky et al, 2013;Wiegerinck et al, 2014). These studies all point to regulation of apical membrane delivery through the recycling endosome system as being crucial to the establishment of apical membrane specializations.…”

Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations

“…Although FHL is primarily characterized as a defect of the immune system, FHL5 patients display additional intestinal symptoms, such as severe noninflammatory diarrhea, which persists after HSCT (11,12). A recent study reported five patients with FHL5 and gastrointestinal symptoms (chronic diarrhea, gastroesophageal reflux, and abdominal pain) displaying ultrastructural features reminiscent of microvillus inclusion disease (MVID) (12).…”

“…A recent study reported five patients with FHL5 and gastrointestinal symptoms (chronic diarrhea, gastroesophageal reflux, and abdominal pain) displaying ultrastructural features reminiscent of microvillus inclusion disease (MVID) (12). MVID is a rare, congenital enteropathy, which is also inherited autosomal recessively (13,14).…”