|
Title
|
|
|
|
Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12
| |
|
Author
|
|
|
|
| |
|
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, 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. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
The journal of clinical investigation. - New York, N.Y., 1924, currens
| |
|
Publication
|
|
|
|
New York, N.Y.
:
2012
| |
|
ISSN
|
|
|
|
0021-9738
[print]
1558-8238
[online]
| |
|
DOI
|
|
|
|
10.1172/JCI60560
| |
|
Volume/pages
|
|
|
|
122
:2
(2012)
, p. 538-544
| |
|
ISI
|
|
|
|
000299765800020
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (open access)
|
|
|
|
| |
|