Document Detail

Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12.
MedLine Citation:
PMID:  22232211     Owner:  NLM     Status:  MEDLINE    
Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules - receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST) - have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12). These autosomal dominant mutations included a complete deletion of RTN2 and a frameshift mutation predicted to produce a highly truncated protein. Wild-type reticulon 2, but not the truncated protein potentially encoded by the frameshift allele, localized to the ER. RTN2 interacted with spastin, and this interaction required a hydrophobic region in spastin that is involved in ER localization and that is predicted to form a curvature-inducing/sensing hairpin loop domain. Our results directly implicate a reticulon protein in axonopathy, show that this protein participates in a network of interactions among HSP proteins involved in ER shaping, and further support the hypothesis that abnormal ER morphogenesis is a pathogenic mechanism in HSP.
Gladys Montenegro; Adriana P Rebelo; James Connell; Rachel Allison; Carla Babalini; Michela D'Aloia; Pasqua Montieri; Rebecca Schüle; Hiroyuki Ishiura; Justin Price; Alleene Strickland; Michael A Gonzalez; Lisa Baumbach-Reardon; Tine Deconinck; Jia Huang; Giorgio Bernardi; Jeffery M Vance; Mark T Rogers; Shoji Tsuji; Peter De Jonghe; Margaret A Pericak-Vance; Ludger Schöls; Antonio Orlacchio; Evan Reid; Stephan Züchner
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-01-09
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-01     Completed Date:  2012-04-20     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  538-44     Citation Subset:  AIM; IM    
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MeSH Terms
Adenosine Triphosphatases / genetics,  metabolism
DNA Mutational Analysis
Endoplasmic Reticulum / metabolism,  ultrastructure*
HEK293 Cells
HeLa Cells
Membrane Proteins / genetics*,  metabolism
Muscle Proteins / genetics*,  metabolism
Nerve Tissue Proteins / genetics*,  metabolism
Spastic Paraplegia, Hereditary / genetics*,  pathology*,  physiopathology
Grant Support
079895//Wellcome Trust; 082381//Wellcome Trust; 082381//Wellcome Trust; GGP10121//Telethon; R01NS054132/NS/NINDS NIH HHS; R01NS072248/NS/NINDS NIH HHS
Reg. No./Substance:
0/Membrane Proteins; 0/Muscle Proteins; 0/Nerve Tissue Proteins; 0/RTN2 protein, human; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.1.-/SPAST protein, human

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