An Amish founder mutation disrupts a PI(3)P-WHAMM-Arp2/3 complex-driven autophagosomal remodeling pathway.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620449
Title:
An Amish founder mutation disrupts a PI(3)P-WHAMM-Arp2/3 complex-driven autophagosomal remodeling pathway.
Authors:
Mathiowetz, A. J.; Baple, E.; Russo, A. J.; Coulter, A. M.; Carrano, E.; Brown, J. D.; Jinks, R. N.; Crosby, Andrew H.; Campellone, K. G.
Abstract:
Actin nucleation factors function to organize, shape, and move membrane-bound organelles, yet they remain poorly defined in relation to disease. Galloway-Mowat syndrome (GMS) is an inherited disorder characterized by microcephaly and nephrosis resulting from mutations in the WDR73 gene. This core clinical phenotype appears frequently in the Amish, where virtually all affected individuals harbor homozygous founder mutations in WDR73 as well as the closely linked WHAMM gene, which encodes a nucleation factor. Here we show that patient cells with both mutations exhibit cytoskeletal irregularities and severe defects in autophagy. Reintroduction of wild-type WHAMM restored autophagosomal biogenesis to patient cells, while inactivation of WHAMM in healthy cell lines inhibited lipidation of the autophagosomal protein LC3 and clearance of ubiquitinated protein aggregates. Normal WHAMM function involved binding to the phospholipid PI(3)P and promoting actin nucleation at nascent autophagosomes. These results reveal a cytoskeletal pathway controlling autophagosomal remodeling and illustrate several molecular processes that are perturbed in Amish GMS patients.
Citation:
An Amish founder mutation disrupts a PI(3)P-WHAMM-Arp2/3 complex-driven autophagosomal remodeling pathway. 2017, 28 (19):2492-2507 Mol. Biol. Cell
Publisher:
American Society for Cell Biology
Journal:
Molecular Biology of the Cell
Issue Date:
15-Sep-2017
URI:
http://hdl.handle.net/11287/620449
DOI:
10.1091/mbc.E17-01-0022
PubMed ID:
28720660
Additional Links:
http://www.molbiolcell.org/cgi/pmidlookup?view=long&pmid=28720660
Type:
Journal Article
Language:
en
ISSN:
1939-4586
Appears in Collections:
Honorary contracts publications; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorMathiowetz, A. J.en
dc.contributor.authorBaple, E.en
dc.contributor.authorRusso, A. J.en
dc.contributor.authorCoulter, A. M.en
dc.contributor.authorCarrano, E.en
dc.contributor.authorBrown, J. D.en
dc.contributor.authorJinks, R. N.en
dc.contributor.authorCrosby, Andrew H.en
dc.contributor.authorCampellone, K. G.en
dc.date.accessioned2017-10-13T15:12:49Z-
dc.date.available2017-10-13T15:12:49Z-
dc.date.issued2017-09-15-
dc.identifier.citationAn Amish founder mutation disrupts a PI(3)P-WHAMM-Arp2/3 complex-driven autophagosomal remodeling pathway. 2017, 28 (19):2492-2507 Mol. Biol. Cellen
dc.identifier.issn1939-4586-
dc.identifier.pmid28720660-
dc.identifier.doi10.1091/mbc.E17-01-0022-
dc.identifier.urihttp://hdl.handle.net/11287/620449-
dc.description.abstractActin nucleation factors function to organize, shape, and move membrane-bound organelles, yet they remain poorly defined in relation to disease. Galloway-Mowat syndrome (GMS) is an inherited disorder characterized by microcephaly and nephrosis resulting from mutations in the WDR73 gene. This core clinical phenotype appears frequently in the Amish, where virtually all affected individuals harbor homozygous founder mutations in WDR73 as well as the closely linked WHAMM gene, which encodes a nucleation factor. Here we show that patient cells with both mutations exhibit cytoskeletal irregularities and severe defects in autophagy. Reintroduction of wild-type WHAMM restored autophagosomal biogenesis to patient cells, while inactivation of WHAMM in healthy cell lines inhibited lipidation of the autophagosomal protein LC3 and clearance of ubiquitinated protein aggregates. Normal WHAMM function involved binding to the phospholipid PI(3)P and promoting actin nucleation at nascent autophagosomes. These results reveal a cytoskeletal pathway controlling autophagosomal remodeling and illustrate several molecular processes that are perturbed in Amish GMS patients.en
dc.language.isoenen
dc.publisherAmerican Society for Cell Biologyen
dc.relation.urlhttp://www.molbiolcell.org/cgi/pmidlookup?view=long&pmid=28720660en
dc.rightsArchived with thanks to Molecular biology of the cellen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleAn Amish founder mutation disrupts a PI(3)P-WHAMM-Arp2/3 complex-driven autophagosomal remodeling pathway.en
dc.typeJournal Articleen
dc.identifier.journalMolecular Biology of the Cellen
dc.type.versionPublisheden

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