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

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 & 5 others Margaret A Pericak-Vance, Ludger Schöls, Antonio Orlacchio, Evan Reid, Stephan L Zuchner

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Abstract

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, lengthdependent 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.

Original languageEnglish
Pages (from-to)538-544
Number of pages7
JournalJournal of Clinical Investigation
Volume122
Issue number2
DOIs
StatePublished - Feb 1 2012

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Hereditary Spastic Paraplegia
Axons
Mutation
Proteins
Paraplegia
North America
Exome
Pyramidal Tracts
Frameshift Mutation
Muscle Spasticity
Morphogenesis
Alleles

ASJC Scopus subject areas

  • Medicine(all)

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Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. / 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; Zuchner, Stephan L.

In: Journal of Clinical Investigation, Vol. 122, No. 2, 01.02.2012, p. 538-544.

Research output: Contribution to journalArticle

Montenegro, G, Rebelo, AP, Connell, J, Allison, R, Babalini, C, D'Aloia, M, Montieri, P, Schüle, R, Ishiura, H, Price, J, Strickland, A, Gonzalez, MA, Baumbach-Reardon, L, Deconinck, T, Huang, J, Bernardi, G, Vance, JM, Rogers, MT, Tsuji, S, De Jonghe, P, Pericak-Vance, MA, Schöls, L, Orlacchio, A, Reid, E & Zuchner, SL 2012, 'Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12', Journal of Clinical Investigation, vol. 122, no. 2, pp. 538-544. https://doi.org/10.1172/JCI60560
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 ; Zuchner, Stephan L. / Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 2. pp. 538-544.
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AU - Montenegro, Gladys

AU - Rebelo, Adriana P.

AU - Connell, James

AU - Allison, Rachel

AU - Babalini, Carla

AU - D'Aloia, Michela

AU - Montieri, Pasqua

AU - Schüle, Rebecca

AU - Ishiura, Hiroyuki

AU - Price, Justin

AU - Strickland, Alleene

AU - Gonzalez, Michael A.

AU - Baumbach-Reardon, Lisa

AU - Deconinck, Tine

AU - Huang, Jia

AU - Bernardi, Giorgio

AU - Vance, Jeffery M

AU - Rogers, Mark T.

AU - Tsuji, Shoji

AU - De Jonghe, Peter

AU - Pericak-Vance, Margaret A

AU - Schöls, Ludger

AU - Orlacchio, Antonio

AU - Reid, Evan

AU - Zuchner, Stephan L

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N2 - 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, lengthdependent 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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