| Structural highlights
Disease
[ATLA1_HUMAN] Hereditary sensory and autonomic neuropathy type 1;Autosomal dominant spastic paraplegia type 3. Spastic paraplegia autosomal dominant 3 (SPG3) [MIM:182600]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Hereditary sensory neuropathy 1D (HSN1D) [MIM:613708]: A disease characterized by adult-onset distal axonal sensory neuropathy leading to mutilating ulcerations as well as hyporeflexia. Some patients may show features suggesting upper neuron involvement. Note=The disease is caused by mutations affecting the gene represented in this entry.[11]
Function
[ATLA1_HUMAN] GTPase tethering membranes through formation of trans-homooligomer and mediating homotypic fusion of endoplasmic reticulum membranes. Functions in endoplasmic reticulum tubular network biogenesis. May also regulate Golgi biogenesis. May regulate axonal development.[12] [13] [14] [15]
Publication Abstract from PubMed
Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of neuropathies affecting upper motor neurons and causing progressive gait disorder. Mutations in the gene SPG3A/atlastin-1 (ATL1), encoding a dynamin superfamily member, which utilizes the energy from GTP hydrolysis for membrane tethering and fusion to promote the formation of a highly branched, smooth endoplasmic reticulum (ER), account for approximately 10% of all HSP cases. The continued discovery and characterization of novel disease mutations are crucial for our understanding of HSP pathogenesis and potential treatments. Here, we report a novel disease-causing, in-frame insertion in the ATL1 gene, leading to inclusion of an additional asparagine residue at position 417 (N417ins). This mutation correlates with complex, early-onset spastic quadriplegia affecting all four extremities, generalized dystonia, and a thinning of the corpus callosum. We show using limited proteolysis and FRET-based studies that this novel insertion affects a region in the protein central to intramolecular interactions and GTPase-driven conformational change, and that this insertion mutation is associated with an aberrant prehydrolysis state. While GTPase activity remains unaffected by the insertion, membrane tethering is increased, indicative of a gain-of-function disease mechanism uncommon for ATL1-associated pathologies. In conclusion, our results identify a novel insertion mutation with altered membrane tethering activity that is associated with spastic quadriplegia, potentially uncovering a broad spectrum of molecular mechanisms that may affect neuronal function.
A novel insertion mutation in atlastin 1 is associated with spastic quadriplegia, increased membrane tethering, and aberrant conformational switching.,Kelly CM, Zeiger PJ, Narayanan V, Ramsey K, Sondermann H J Biol Chem. 2022 Jan;298(1):101438. doi: 10.1016/j.jbc.2021.101438. Epub 2021, Nov 19. PMID:34808209[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Namekawa M, Muriel MP, Janer A, Latouche M, Dauphin A, Debeir T, Martin E, Duyckaerts C, Prigent A, Depienne C, Sittler A, Brice A, Ruberg M. Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis. Mol Cell Neurosci. 2007 May;35(1):1-13. Epub 2007 Jan 26. PMID:17321752 doi:10.1016/j.mcn.2007.01.012
- ↑ Zhao X, Alvarado D, Rainier S, Lemons R, Hedera P, Weber CH, Tukel T, Apak M, Heiman-Patterson T, Ming L, Bui M, Fink JK. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet. 2001 Nov;29(3):326-31. PMID:11685207 doi:10.1038/ng758
- ↑ Muglia M, Magariello A, Nicoletti G, Patitucci A, Gabriele AL, Conforti FL, Mazzei R, Caracciolo M, Ardito B, Lastilla M, Tedeschi G, Quattrone A. Further evidence that SPG3A gene mutations cause autosomal dominant hereditary spastic paraplegia. Ann Neurol. 2002 Jun;51(6):794-5. PMID:12112092 doi:10.1002/ana.10185
- ↑ Dalpozzo F, Rossetto MG, Boaretto F, Sartori E, Mostacciuolo ML, Daga A, Bassi MT, Martinuzzi A. Infancy onset hereditary spastic paraplegia associated with a novel atlastin mutation. Neurology. 2003 Aug 26;61(4):580-1. PMID:12939451
- ↑ Sauter SM, Engel W, Neumann LM, Kunze J, Neesen J. Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus. Hum Mutat. 2004 Jan;23(1):98. PMID:14695538 doi:10.1002/humu.9205
- ↑ D'Amico A, Tessa A, Sabino A, Bertini E, Santorelli FM, Servidei S. Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene. Neurology. 2004 Jun 8;62(11):2138-9. PMID:15184642
- ↑ Rainier S, Sher C, Reish O, Thomas D, Fink JK. De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy. Arch Neurol. 2006 Mar;63(3):445-7. PMID:16533974 doi:10.1001/archneur.63.3.445
- ↑ Meijer IA, Dion P, Laurent S, Dupre N, Brais B, Levert A, Puymirat J, Rioux MF, Sylvain M, Zhu PP, Soderblom C, Stadler J, Blackstone C, Rouleau GA. Characterization of a novel SPG3A deletion in a French-Canadian family. Ann Neurol. 2007 Jun;61(6):599-603. PMID:17427918 doi:10.1002/ana.21114
- ↑ Alvarez V, Sanchez-Ferrero E, Beetz C, Diaz M, Alonso B, Corao AI, Gamez J, Esteban J, Gonzalo JF, Pascual-Pascual SI, Lopez de Munain A, Moris G, Ribacoba R, Marquez C, Rosell J, Marin R, Garcia-Barcina MJ, Del Castillo E, Benito C, Coto E. Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia. BMC Neurol. 2010 Oct 8;10:89. doi: 10.1186/1471-2377-10-89. PMID:20932283 doi:10.1186/1471-2377-10-89
- ↑ McCorquodale DS 3rd, Ozomaro U, Huang J, Montenegro G, Kushman A, Citrigno L, Price J, Speziani F, Pericak-Vance MA, Zuchner S. Mutation screening of spastin, atlastin, and REEP1 in hereditary spastic paraplegia. Clin Genet. 2011 Jun;79(6):523-30. doi: 10.1111/j.1399-0004.2010.01501.x. PMID:20718791 doi:10.1111/j.1399-0004.2010.01501.x
- ↑ Guelly C, Zhu PP, Leonardis L, Papic L, Zidar J, Schabhuttl M, Strohmaier H, Weis J, Strom TM, Baets J, Willems J, De Jonghe P, Reilly MM, Frohlich E, Hatz M, Trajanoski S, Pieber TR, Janecke AR, Blackstone C, Auer-Grumbach M. Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. Am J Hum Genet. 2011 Jan 7;88(1):99-105. doi: 10.1016/j.ajhg.2010.12.003. Epub, 2010 Dec 30. PMID:21194679 doi:10.1016/j.ajhg.2010.12.003
- ↑ Zhu PP, Patterson A, Lavoie B, Stadler J, Shoeb M, Patel R, Blackstone C. Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin. J Biol Chem. 2003 Dec 5;278(49):49063-71. Epub 2003 Sep 23. PMID:14506257 doi:10.1074/jbc.M306702200
- ↑ Namekawa M, Muriel MP, Janer A, Latouche M, Dauphin A, Debeir T, Martin E, Duyckaerts C, Prigent A, Depienne C, Sittler A, Brice A, Ruberg M. Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis. Mol Cell Neurosci. 2007 May;35(1):1-13. Epub 2007 Jan 26. PMID:17321752 doi:10.1016/j.mcn.2007.01.012
- ↑ Rismanchi N, Soderblom C, Stadler J, Zhu PP, Blackstone C. Atlastin GTPases are required for Golgi apparatus and ER morphogenesis. Hum Mol Genet. 2008 Jun 1;17(11):1591-604. doi: 10.1093/hmg/ddn046. Epub 2008 Feb, 12. PMID:18270207 doi:10.1093/hmg/ddn046
- ↑ Hu J, Shibata Y, Zhu PP, Voss C, Rismanchi N, Prinz WA, Rapoport TA, Blackstone C. A class of dynamin-like GTPases involved in the generation of the tubular ER network. Cell. 2009 Aug 7;138(3):549-61. PMID:19665976 doi:S0092-8674(09)00628-X
- ↑ Kelly CM, Zeiger PJ, Narayanan V, Ramsey K, Sondermann H. A novel insertion mutation in atlastin 1 is associated with spastic quadriplegia, increased membrane tethering, and aberrant conformational switching. J Biol Chem. 2022 Jan;298(1):101438. doi: 10.1016/j.jbc.2021.101438. Epub 2021, Nov 19. PMID:34808209 doi:http://dx.doi.org/10.1016/j.jbc.2021.101438
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