# 608030
AMYOTROPHIC LATERAL SCLEROSIS 6 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS6
ORPHA: 803, 275872; DO: 0060198;
Phenotype-Gene Relationships
| Location | Phenotype | Phenotype MIM number |
Inheritance | Phenotype mapping key |
Gene/Locus | Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p11.2 | Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia | 608030 | 3 | FUS | 137070 |
TEXT
A number sign (#) is used with this entry because amyotrophic lateral sclerosis-6 with or without frontotemporal dementia (ALS6) is caused by heterozygous mutation in the FUS gene (137070) on chromosome 16p11.2. Homozygous mutation in the FUS gene was found in one family with ALS6.
Heterozygous mutation in the FUS gene can also cause hereditary essential tremor-4 (ETM4; 614782).
For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
For a phenotypic description and a discussion of genetic heterogeneity of frontotemporal dementia, see FTD (600274).
Clinical Features
Vance et al. (2009) reported 8 families with ALS due to mutations in the FUS gene. Among 20 affected individuals, there was even gender distribution, the average age at onset was 44.5 years, and the average survival was 33 months. The site of onset varied: it was cervical in 10, lumbar in 5, and bulbar in 3. No affected individual developed cognitive deficits. Detailed neuropathologic examination of 3 patients showed severe lower motor neuron loss in the spinal cord, and to a lesser degree in the brain stem, whereas dorsal horn neurons appeared unaffected. There was evidence of mild myelin loss in the dorsal columns, but only 1 case had major pallor of the corticospinal tracts. There was mild to moderate upper motor neuron loss in the motor cortex. FUS immunostaining showed large globular and elongated cytoplasmic inclusions in spinal cord motor neurons and dystrophic neurites in all cases.
Hewitt et al. (2010) reported a 69-year-old man who presented with predominantly lower motor neuron ALS involving both the lower and upper limbs. He had marked proximal muscle wasting with fasciculations around the shoulder girdle and depressed reflexes. The lower limbs showed distal weakness, proximal fasciculations, and decreased reflexes. He had no family history of neurologic disease, and died of respiratory failure 42 months after symptom onset. Postmortem examination showed marked loss of lower motor neurons at all spinal levels, and neuronal and glial cytoplasmic inclusions that stained for FUS. Hewitt et al. (2010) also reported an unrelated man who had onset of a progressive muscular atrophy variant of motor neuron disease with upper limb onset at the age of 61 years. His brother presented with a similar pattern of disease at age 58, but DNA was not available. Postmortem examination of the first patient showed marked depletion of lower motor neurons with glial cytoplasmic and nuclear inclusions that stained for p62 (SQSTM1; 601530). There was FUS staining predominantly in the nucleus of neurons and glia, with some lower motor neurons showing strong cytoplasmic FUS expression.
Yan et al. (2010) summarized the clinical features of 101 patients from 25 unrelated families with ALS6 who carried heterozygous mutations in the FUS gene. The average age at symptom onset was 43.6 years, which was earlier than that observed in patients with SOD1 (147450) or TARDBP (605078) mutations. Some patients with FUS mutations had onset in adolescence. The average duration of symptoms for those with FUS mutations was 3.4 years, with 88.6% of patients dying in less than 4 years, indicating a more rapid disease progression compared to those with SOD1 or TARDBP mutations. Approximately 33.3% of those with FUS mutations presented with bulbar onset, and some affected members of 3 families also developed frontotemporal dementia.
Mapping
Sapp et al. (2003) performed a linkage screen in 16 U.S. pedigrees with familial ALS and no evidence for mutations in the SOD1 gene (147450). In 1 family, they identified a novel ALS locus, designated ALS6, spanning 51 cM (38 Mb) on chromosome 16p12.1-q21. In another family, they identified a novel locus on chromosome 20p (ALS7; 608031).
Ruddy et al. (2003) performed genomewide linkage analysis in a large European family (F1) with ALS and without SOD1 mutation or linkage to known ALS loci. Haplotype analysis in family F1 narrowed the locus to an approximately 30-cM region flanked by markers D16S3075 and D16S3112. Subsequently, Vance et al. (2009) repeated the genomewide scan using SNPs and 2 additional affected family members and confirmed the linkage to chromosome 16.
Genetic Heterogeneity
Abalkhail et al. (2003) performed a genome screen of U.K. ALS families lacking SOD1 mutations and identified a putative locus on chromosome 16q12.1-q12.2. They refined the assignment to a 14.74-cM (6.6-Mb) interval.
Ruddy et al. (2003) performed a genomewide linkage screen in a large European family (F2) with ALS without SOD1 mutations or linkage to known ALS loci. Haplotype analysis of family F2 narrowed the locus to a 10.1-cM (4.5-Mb) region flanked by markers D16S3396 and D16S3112 on chromosome 16q12-q13, containing 18 genes and 70 predicted genes.
Molecular Genetics
In 17 different families with ALS6, including 2 families previously reported by Sapp et al. (2003), Kwiatkowski et al. (2009) identified 13 different mutations in the FUS gene (see, e.g., 137070.0001-137070.0004), including 10 mutations in exon 15. One of the families was consanguineous and from Cape Verde, an island off the western coast of Africa; this family had a homozygous mutation (H517Q; 137070.0001) and showed autosomal recessive inheritance. All of the other families had heterozygous mutations and showed autosomal dominant inheritance. Another family had been reported by Sapp et al. (2003). Postmortem examination of 1 patient with the R521G mutation (137070.0002) showed loss of motor neurons in the anterior horn of the spinal cord and the hypoglossal nucleus. Immunostaining showed nuclear and cytoplasmic aggregation of FUS and diffuse ubiquitin positivity in nuclei in the patient tissue, but not control tissue, suggesting misfolding of a nuclear protein. In vitro RNA binding studies showed that the mutations did not affect binding of RNA oligomers.
Vance et al. (2009) identified 3 FUS mutations in 9 families with ALS6. All of the mutations had also been found by Kwiatkowski et al. (2009). One of the families (F1) had been reported by Ruddy et al. (2003). Vance et al. (2009) demonstrated that wildtype endogenous FUS is predominantly localized to the nucleus. FUS mutations caused subcellular mislocalization with protein retention in the cytoplasm. Kwiatkowski et al. (2009) and Vance et al. (2009) estimated the frequency of FUS mutations to be about 5% in familial ALS.
Belzil et al. (2009) identified heterozygous FUS mutations (see, e.g., 137070.0004-137070.0005) in 1 (1.25%) of 80 patients with familial ALS and in 3 (0.74%) of 405 patients with apparently sporadic ALS. Three of the 4 mutations occurred in exon 15. Age at onset ranged from 32 to 80 years, and none had cognitive impairment; the patients were of French and French Canadian origin.
Ticozzi et al. (2009) identified 4 different FUS mutations, including 2 novel mutations, in 5 (4%) of 97 Italian patients with familial ALS. The authors noted that all affected individuals had early symptoms of symmetric weakness in the proximal muscles. One patient developed dementia.
Corrado et al. (2010) identified 7 different missense mutations, including 6 novel mutations, in the FUS gene (see, e.g., 137070.0006 and 137070.0007) in 9 of 1,009 Italian patients with ALS, including 964 patients with sporadic disease. Two of the 9 patients with an FUS mutation had a family history of the disorder. In addition, 8 different deletions and 2 insertions were identified in 2 glycine-rich regions in exons 5 and 6, but these were also found in controls and believed to represent triplet repeat length polymorphisms. Overall, pathogenic FUS mutations were found in 0.7% of sporadic and 4.4% of familial ALS in this population.
Hewitt et al. (2010) identified a heterozygous mutation in the FUS gene (137070.0008) in 2 (5%) of 42 patients with familial ALS. A different heterozygous mutation (137070.0006) was identified in 1 of 548 patients with sporadic ALS. Both mutations were located in the C-terminal region of the protein, which is important in regulating DNA and RNA binding. Hewitt et al. (2010) postulated that disruption of this region may disrupt subcellular distribution of FUS, in turn affecting transcription and RNA processing and conferring a toxic gain of function.
Millecamps et al. (2010) identified 5 different FUS mutations in 7 (4.3%) of 162 French probands with familial ALS. All mutations were located in exon 15 of the FUS gene. One patient with a FUS mutation (R521C; 137070.0004) was also heterozygous for a mutation in the ANG gene (K17I; 105850.0002), which causes ALS9 (611895). Overall, FUS mutation carriers had an earlier age of disease onset and shorter life span due to a rapid disease progression compared to those with mutations in other ALS genes. The site of onset of FUS patients was in the arms (43%), legs (38%), or bulbar muscles (19%). One patient developed cognitive impairment 5 months after the onset of ALS.
Waibel et al. (2010) identified 2 different heterozygous mutations in the FUS gene (see, e.g., R495X; 137070.0009) in 4 (6.8%) of 58 German families with ALS. No FUS mutations were found in 133 patients with sporadic disease. The authors sequenced only the C-terminal region of the gene encompassing exons 13 to 15.
Yan et al. (2010) identified 16 heterozygous FUS mutations, including 11 novel mutations (see, e.g., 137070.0010), in 25 (5.6%) of 476 patients with familial ALS who did not have mutations in the SOD1 (147450) or TARDBP (605078) genes. All exons of the FUS gene were screened, but 12 of the 16 mutations occurred in exons 14 and 15. No mutations were found in 41 patients with sporadic ALS.
Pathogenesis
In multiple cell lines, Ito et al. (2011) found that wildtype FUS is modified and/or cleaved posttranslationally to produce fragments of various sizes. Immunofluorescent studies showed localization of wildtype FUS to the nucleus, whereas mutant FUS formed inclusion bodies in the cytoplasm and neurites of 5 to 13% of cells. These inclusion bodies did not show evidence of ubiquitination or direct interaction with TARDBP, but did show features of stress granules, which are cellular structures that package mRNA and RNA-binding proteins during cell stress. Deletion constructs indicated that the C-terminal FUS is critical for subcellular distribution and nuclear localization, which is mediated by Ran GTPase (RAN1; 601179)-dependent machinery. Lack of the C terminus resulted in the formation of stress granules. Ito et al. (2011) concluded that the pathogenesis of ALS6 involves disruption of the nuclear transport of FUS and cytoplasmic accumulation of FUS and stress granules, which results in cellular toxicity and neurodegeneration.
Nomenclature
Mackenzie et al. (2010) suggested that neuropathologic term 'FTLD-FUS' be used for frontotemporal lobar degeneration with FUS-immunopositive inclusions.
REFERENCES
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Kwiatkowski, T. J., Jr., Bosco, D. A., LeClerc, A.L., Tamrazian, E., Vanderburg, C. R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E. J., Munsat, T., Valdmanis, P., Rouleau, G. A., and 14 others. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323: 1205-1208, 2009. Note: Erratum: Science 324: 465 only, 2009. [PubMed: 19251627] [Full Text: http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=19251627]
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Mackenzie, I. R. A., Neumann, M., Bigio, E. H., Cairns, N. J., Alafuzoff, I., Kril, J., Kovacs, G. G., Ghetti, B., Halliday, G., Holm, I. E., Ince, P. G., Kamphorst, W., and 9 others. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropath. 119: 1-4, 2010. [PubMed: 19924424] [Full Text: https://dx.doi.org/10.1007/s00401-009-0612-2]
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Yan, J., Deng, H.-X., Siddique, N., Fecto, F., Chen, W., Yang, Y., Liu, E., Donkervoort, S., Zheng, J. G., Shi, Y., Ahmeti, K. B., Brooks, B., Engel, W. K., Siddique, T. Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology 75: 807-814, 2010. [PubMed: 20668259] [Full Text: http://www.neurology.org/cgi/pmidlookup?view=long&pmid=20668259]
Cassandra L. Kniffin - updated : 1/28/2011
Cassandra L. Kniffin - updated : 12/15/2010
Cassandra L. Kniffin - updated : 9/28/2010
Cassandra L. Kniffin - updated : 8/16/2010
Cassandra L. Kniffin - updated : 6/22/2010
Cassandra L. Kniffin - updated : 9/1/2009
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