A dominant negative variant of <i>RAB5B</i> disrupts maturation of surfactant protein B and surfactant protein C-Reference-Cited by-同舟云学术

A dominant negative variant of RAB5B disrupts maturation of surfactant protein B and surfactant protein C

Published:2022-02-04 Issue:6 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Huang Huiyan¹^ORCID,Pan Jiehong²^ORCID,Spielberg David R.³^ORCID,Hanchard Neil A.⁴,Scott Daryl A.⁴⁵^ORCID,Burrage Lindsay C.⁴^ORCID,Dai Hongzheng⁴,Murdock David⁴,Rosenfeld Jill A.⁴^ORCID,Mohammad Ariz⁶^ORCID,Huang Tao²^ORCID,Lindsey Anika G.¹^ORCID,Kim Hyori¹^ORCID,Chen Jian⁶^ORCID,Ramu Avinash⁶^ORCID,Morrison Stephanie A.¹,Dawson Zachary D.¹^ORCID,Hu Alex Z.¹^ORCID,Tycksen Eric⁷^ORCID,Silverman Gary A.¹^ORCID,Baldridge Dustin¹⁶^ORCID,Wambach Jennifer A.¹,Pak Stephen C.¹^ORCID,Brody Steven L.²^ORCID,Schedl Tim⁶^ORCID,

Affiliation:

1. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110

2. Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110

3. Department of Pediatrics, Section of Pulmonary Medicine, Baylor College of Medicine, Houston, TX 77030

4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030

5. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030

6. Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110

7. Genome Technology Access Center, McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110

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.

Funder

HHS | NIH | NIH Office of the Director

HHS | NIH | National Institute of General Medical Sciences

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2105228119

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