Journal Article

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

Ishiura, Hiroyuki, Rogers, Mark T., Züchner, Stephan, Rebelo, Adriana P., Connell, James, Allison, Rachel, Strickland, Alleene, Baumbach-Reardon, Lisa, Bernardi, Giorgio, Vance, Jeffery M., Schöls, Ludger, Schüle, Rebecca, De Jonghe, Peter, Deconinck, Tine, Montieri, Pasqua, Babalini, Carla, Orlacchio, Antonio, Price, Justin, Tsuji, Shoji, Reid, Evan, Montenegro, Gladys, Huang, Jia, D’Aloia, Michela, Gonzalez, Michael A., Pericak-Vance, Margaret A.

2012

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: 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