A dominant negative variant of <i>RAB5B</i> disrupts maturation of surfactant protein B and surfactant protein C
Huiyan Huang, Jiehong Pan, David R. Spielberg, Neil A. Hanchard, Daryl A. Scott, Lindsay C. Burrage, Hongzheng Dai, David R. Murdock, Jill A. Rosenfeld, Ariz Mohammad, Tao Huang, Anika Lindsey, Hyori Kim, Jian Chen, Avinash Ramu, Stephanie A. Morrison, Zachary Dawson, Alex Z. Hu, Eric Tycksen, Gary A. Silverman, Dustin Baldridge, Jennifer Wambach, Undiagnosed Diseases Network, Stephen C. Pak, Steven L. Brody, Tim Schedl
Abstract
Significance The Rab5 GTPase functions in early endosome (EE) fusion in the endocytic pathway. Here, we propose that RAB5B also has a noncanonical vesicular fusion function in the regulated secretion pathway that produces mature surfactant proteins SP-B and SP-C in the lung. This function was revealed from investigation of a proband with interstitial lung disease suggestive of a surfactant dysfunction disorder who carried a de novo Asp136His variant in the RAB5B gene. Our modeling in C. elegans provided information on the genetic and cell biological mechanism, and analyses of proband and normal lung biopsies suggested a function for RAB5B and EEs in surfactant protein processing/trafficking. This work indicates that RAB5B p.Asp136His causes a surfactant dysfunction disorder.