| Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. | |
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MedLine Citation:
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PMID: 22232211 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2012-1-9 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: - ISSN: 1558-8238 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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