Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mut...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Association
for the Advancement
of Science
2017
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| _version_ | 1826258261335080960 |
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| author | Smith, BN Topp, SD Fallini, C Shibata, H Chen, HJ Troakes, C King, A Ticozzi, N Kenna, KP Soragia-Gkazi, A Miller, JW Sato, A Dias, DM Jeon, M Vance, C Wong, CH de Majo, M Kattuah, W Mitchell, JC Scotter, EL Parkin, NW Sapp, PC Nolan, M Nestor, PJ Simpson, M Weale, M Lek, M Baas, F de Jong, JM Asbroek, ALMA Redondo, AG Esteban-Pérez, J Tiloca, C Verde, F Duga, S Leigh, N Pall, H Morrison, KE Al-Chalabi, A Shaw, PJ Kirby, J Turner, MR Talbot, K Hardiman, O Glass, JD De Belleroche, J Maki, M Moss, SE Miller, C Gellera, C Ratti, A Al-Sarraj, S Brown, RH Silani, V Landers, JE Shaw, CE |
| author_facet | Smith, BN Topp, SD Fallini, C Shibata, H Chen, HJ Troakes, C King, A Ticozzi, N Kenna, KP Soragia-Gkazi, A Miller, JW Sato, A Dias, DM Jeon, M Vance, C Wong, CH de Majo, M Kattuah, W Mitchell, JC Scotter, EL Parkin, NW Sapp, PC Nolan, M Nestor, PJ Simpson, M Weale, M Lek, M Baas, F de Jong, JM Asbroek, ALMA Redondo, AG Esteban-Pérez, J Tiloca, C Verde, F Duga, S Leigh, N Pall, H Morrison, KE Al-Chalabi, A Shaw, PJ Kirby, J Turner, MR Talbot, K Hardiman, O Glass, JD De Belleroche, J Maki, M Moss, SE Miller, C Gellera, C Ratti, A Al-Sarraj, S Brown, RH Silani, V Landers, JE Shaw, CE |
| author_sort | Smith, BN |
| collection | OXFORD |
| description | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases (P = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11-positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing ANXA11 with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in ANXA11 are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis. |
| first_indexed | 2024-03-06T18:31:10Z |
| format | Journal article |
| id | oxford-uuid:09b3522e-fa85-4747-9815-478ac8322a9d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:31:10Z |
| publishDate | 2017 |
| publisher | American Association
for the Advancement
of Science |
| record_format | dspace |
| spelling | oxford-uuid:09b3522e-fa85-4747-9815-478ac8322a9d2022-03-26T09:19:57ZMutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:09b3522e-fa85-4747-9815-478ac8322a9dEnglishSymplectic Elements at OxfordAmerican Association for the Advancement of Science2017Smith, BNTopp, SDFallini, CShibata, HChen, HJTroakes, CKing, ATicozzi, NKenna, KPSoragia-Gkazi, AMiller, JWSato, ADias, DMJeon, MVance, CWong, CHde Majo, MKattuah, WMitchell, JCScotter, ELParkin, NWSapp, PCNolan, MNestor, PJSimpson, MWeale, MLek, MBaas, Fde Jong, JMAsbroek, ALMARedondo, AGEsteban-Pérez, JTiloca, CVerde, FDuga, SLeigh, NPall, HMorrison, KEAl-Chalabi, AShaw, PJKirby, JTurner, MRTalbot, KHardiman, OGlass, JDDe Belleroche, JMaki, MMoss, SEMiller, CGellera, CRatti, AAl-Sarraj, SBrown, RHSilani, VLanders, JEShaw, CEAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases (P = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11-positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing ANXA11 with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in ANXA11 are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis. |
| spellingShingle | Smith, BN Topp, SD Fallini, C Shibata, H Chen, HJ Troakes, C King, A Ticozzi, N Kenna, KP Soragia-Gkazi, A Miller, JW Sato, A Dias, DM Jeon, M Vance, C Wong, CH de Majo, M Kattuah, W Mitchell, JC Scotter, EL Parkin, NW Sapp, PC Nolan, M Nestor, PJ Simpson, M Weale, M Lek, M Baas, F de Jong, JM Asbroek, ALMA Redondo, AG Esteban-Pérez, J Tiloca, C Verde, F Duga, S Leigh, N Pall, H Morrison, KE Al-Chalabi, A Shaw, PJ Kirby, J Turner, MR Talbot, K Hardiman, O Glass, JD De Belleroche, J Maki, M Moss, SE Miller, C Gellera, C Ratti, A Al-Sarraj, S Brown, RH Silani, V Landers, JE Shaw, CE Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis |
| title | Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis |
| title_full | Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis |
| title_fullStr | Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis |
| title_full_unstemmed | Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis |
| title_short | Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis |
| title_sort | mutations in the vesicular trafficking protein annexin a11 are associated with amyotrophic lateral sclerosis |
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