Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 122, Issue 2, Pages 538-544Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI60560
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Funding
- NIH [R01NS072248, R01NS054132]
- Hereditary Spastic Paraplegia Foundation
- Wellcome Trust [082381, 079895]
- Comitato Telethon Fondazione Onlus, Italy [GGP10121]
- Italian Ministero dell'Istruzione, dell'Universita e della Ricerca [020903052]
- Universita di Roma Tor Vergata (FAA) [020903023]
- European Union (E-RARE) [01GM0807]
- Grants-in-Aid for Scientific Research [10J05639] Funding Source: KAKEN
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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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