Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12

• Published in: The Journal of clinical investigation 2012-02, Vol.122 (2), p.538-544
• Main Authors: Montenegro, Gladys, Rebelo, Adriana P, Connell, James, Allison, Rachel, Babalini, Carla, D'Aloia, Michela, Montieri, Pasqua, Schüle, Rebecca, Ishiura, Hiroyuki, Price, Justin, Strickland, Alleene, Gonzalez, Michael A, Baumbach-Reardon, Lisa, Deconinck, Tine, Huang, Jia, Bernardi, Giorgio, Vance, Jeffery M, Rogers, Mark T, Tsuji, Shoji, De Jonghe, Peter, Pericak-Vance, Margaret A, Schöls, Ludger, Orlacchio, Antonio, Reid, Evan, Züchner, Stephan
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Biomedical research; Chromosomes; DNA Mutational Analysis; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Gene mutations; Genes; Genetic aspects; Health aspects; Heat shock proteins; HEK293 Cells; HeLa Cells; Humans; Membrane Proteins - genetics; Membrane Proteins - metabolism; Morphogenesis; Muscle Proteins - genetics; Muscle Proteins - metabolism; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Paralysis; Paralysis, Spastic; Physiological aspects; Proteins; Risk factors; Spastic Paraplegia, Hereditary - genetics; Spastic Paraplegia, Hereditary - pathology; Spastic Paraplegia, Hereditary - physiopathology; Spasticity; Spastin
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci60560

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.