Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12.
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.
Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA.
Gladys
G
Montenegro
Adriana P
AP
Rebelo
James
J
Connell
Rachel
R
Allison
Carla
C
Babalini
Michela
M
D'Aloia
Pasqua
P
Montieri
Rebecca
R
Schüle
Hiroyuki
H
Ishiura
Justin
J
Price
Alleene
A
Strickland
Michael A
MA
Gonzalez
Lisa
L
Baumbach-Reardon
Tine
T
Deconinck
Jia
J
Huang
Giorgio
G
Bernardi
Jeffery M
JM
Vance
Mark T
MT
Rogers
Shoji
S
Tsuji
Peter
P
De Jonghe
Margaret A
MA
Pericak-Vance
Ludger
L
Schöls
Antonio
A
Orlacchio
Evan
E
Reid
Stephan
S
Züchner
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D000074181:Spastin
D008565:Membrane Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; C112025:RTN2 protein, human; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human