# 608627
AMYOTROPHIC LATERAL SCLEROSIS 8; ALS8
ORPHA: 803; DO: 0050752;
Phenotype-Gene Relationships
| Location | Phenotype | Phenotype MIM number |
Inheritance | Phenotype mapping key |
Gene/Locus | Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.32 | Amyotrophic lateral sclerosis 8 | 608627 | Autosomal dominant | 3 | VAPB | 605704 |
TEXT
A number sign (#) is used with this entry because of evidence that ALS8 is caused by heterozygous mutation in the VAPB gene (605704) on chromosome 20q13.3.
For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
Clinical Features
Nishimura et al. (2004) described a Caucasian Brazilian family in which 26 members spanning 3 generations presented with clinical and neurologic signs compatible with the diagnosis of ALS with slow progression. The disorder affected both sexes equally, with no evidence of clinical anticipation. Clinical onset occurred between ages 31 and 45 years, and the cause of death was respiratory failure. Twelve family members were examined. All patients had lower motor neuron symptoms, and 5 also had bulbar involvement.
Chen et al. (2010) reported a 73-year-old man with ALS8, who was not of Brazilian descent. He presented with wasting of the small muscles of the hands. He also had fasciculations of the leg, and later developed speech and swallowing difficulties. The diagnosis was confirmed by nerve conduction studies. The patient had a brother with ALS who died within 4 months of diagnosis from pneumonia, but DNA was not available for testing.
Mapping
Nishimura et al. (2004) performed linkage analysis in the large Brazilian family with atypical ALS and excluded all previously reported ALS loci. They identified a novel locus, here designated ALS8, spanning 2.7 Mb between markers D20S430 and D20S173 on chromosome 20q13.33. Two-point linkage analysis showed a maximum lod score of 6.02 at theta = 0.0 for marker D20S171; multipoint linkage analysis showed a maximum lod score of 7.45 for marker D20S164. No mutations were identified in 3 genes mapping to the ALS8 interval: TUBB1 (612901), CTSZ (603169), and ATP5E (606153). ALS8 is presumably distinct from the form of ALS mapping to chromosome 20p, here designated ALS7 (608031).
Molecular Genetics
Nishimura et al. (2004) found that the autosomal dominant slowly progressive disorder in the large Brazilian family described by Nishimura et al. (2004), characterized by fasciculations, cramps, and postural tremor, was caused by a P56S mutation in the VAPB gene (605704.0001). Subsequently, the same mutation was identified in patients from 6 additional kindreds in which, however, patients demonstrated different clinical courses, such as ALS8, late-onset spinal muscular atrophy (182980), and typical severe ALS with rapid progression. Although it was not possible to link all these families genealogically, haplotype analysis suggested founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have a function in membrane transport. The data suggested that clinically variable motor neuron diseases may be caused by a dysfunction in intracellular membrane trafficking.
Landers et al. (2008) identified the P56S mutation in affected members of a Brazilian family with ALS. The mean age at onset was between 45 and 55 years with survival varying from 5 to 18 years. Mutations in the VAPB gene were not identified in 79 other ALS families. Landers et al. (2008) concluded that VAPB mutations are not a common cause of ALS.
Millecamps et al. (2010) identified the P56S mutation in 1 (0.6%) of 162 French probands with familial ALS. The patient was of Japanese descent, representing the first non-Brazilian reported to carry this mutation. Three other family members had motor neuron disease, suggesting autosomal dominant inheritance. The patient had long disease duration with onset in the legs during the sixth decade. Millecamps et al. (2010) suggested that the finding of the P56S mutation in a Japanese patient may reflect the Portuguese trading connection with the Far East and Brazil in the mid-16th century.
In 1 of 107 non-Brazilian probands with ALS, Chen et al. (2010) identified a heterozygous mutation in the VAPB gene (T46I; 605704.0002). In vitro functional expression studies in COS-7 and neuronal cells showed that the T46I mutation formed intracellular protein aggregates and ubiquitin aggregates, ultimately resulting in cell death. Chen et al. (2010) also postulated that disturbances in lipid metabolism may play a role in the pathogenesis of ALS.
Animal Model
In transgenic mice, Aliaga et al. (2013) found that expression of human VAPB with the ALS8-associated P56S mutation caused various motor behavioral abnormalities, including progressive hyperactivity. Accumulation of mutant VAPB triggered ER stress, leading to increased proapoptotic Chop (DDIT3; 126337) expression in both corticospinal and spinal motor neurons. Mutant transgenic mice experienced significant loss of corticospinal motor neurons, but no obvious degeneration of spinal motor neurons.
REFERENCES
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Aliaga, L., Lai, C., Yu, J., Chub, N., Shim, H., Sun, L., Zie, C., Yang, W.-J., Lin, X., O'Donovan, M. J., Cai, H. Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons. Hum. Molec. Genet. 22: 4293-4305, 2013. Note: Erratum: Hum. Molec. Genet. 23: 3069 only, 2014. [PubMed: 23771029] [Full Text: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddt279]
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Chen, H.-J., Anagnostou, G., Chai, A., Withers, J., Morris, A., Adhikaree, J., Pennetta, G., de Belleroche, J. S. Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. J. Biol. Chem. 285: 40266-40281, 2010. [PubMed: 20940299] [Full Text: http://www.jbc.org/cgi/pmidlookup?view=long&pmid=20940299]
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Landers, J. E., Leclerc, A. L., Shi, L., Virkud, A., Cho, T., Maxwell, M. M., Henry, A. F., Polak, N., Glass, J. D., Kwiatkowski, T. J., Al-Chalabi, A., Shaw, C. E., Leigh, P. N., Rodriguez-Leyza, I., McKenna-Yasek, D., Sapp, P. C., Brown, R. H., Jr. New VAPB deletion variant and exclusion of VAPB mutations in familial ALS. Neurology 70: 1179-1185, 2008. [PubMed: 18322265] [Full Text: http://www.neurology.org/cgi/pmidlookup?view=long&pmid=18322265]
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Millecamps, S., Salachas, F., Cazeneuve, C., Gordon, P., Bricka, B., Camuzat, A., Guillot-Noel, L., Russaouen, O., Bruneteau, G., Pradat, P.-F., Le Forestier, N., Vandenberghe, N., and 14 others. SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations. J. Med. Genet. 47: 554-560, 2010. [PubMed: 20577002] [Full Text: http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=20577002]
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Nishimura, A. L., Mitne-Neto, M., Silva, H. C. A., Oliveira, J. R. M., Vainzof, M., Zatz, M. A novel locus for late onset amyotrophic lateral sclerosis/motor neurone disease variant at 20q13. J. Med. Genet. 41: 315-320, 2004. [PubMed: 15060112] [Full Text: http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=15060112]
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Nishimura, A. L., Mitne-Neto, M., Silva, H. C. A., Richieri-Costa, A., Middleton, S., Cascio, D., Kok, F., Oliveira, J. R. M., Gillingwater, T., Webb, J., Skehel, P., Zatz, M. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am. J. Hum. Genet. 75: 822-831, 2004. [PubMed: 15372378] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63787-2]
Cassandra L. Kniffin - updated : 12/22/2010
Cassandra L. Kniffin - updated : 9/27/2010
Cassandra L. Kniffin - updated : 10/17/2008
Victor A. McKusick - updated : 10/21/2004
mgross : 07/10/2015
wwang : 1/5/2011
ckniffin : 12/22/2010
wwang : 9/29/2010
ckniffin : 9/27/2010
wwang : 9/1/2009
mgross : 7/9/2009
wwang : 10/20/2008
ckniffin : 10/17/2008
alopez : 10/25/2004
terry : 10/21/2004
tkritzer : 4/30/2004
tkritzer : 4/30/2004