SNOMEDCT: 1201950008; ORPHA: 803; DO: 0060195;
Cytogenetic location: 18q21 Genomic coordinates (GRCh38) : 18:45,900,001-63,900,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21 | Amyotrophic lateral sclerosis 3 | 606640 | Autosomal dominant | 2 |
Amyotrophic lateral sclerosis-3 (ALS3) is a neurodegenerative disorder characterized by the death of motor neurons in the cortex, brainstem, and spinal cord, resulting in progressive muscle weakness and atrophy and death from respiratory failure, usually within 3 to 5 years of symptom onset (Brown, 1995).
For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Hand et al. (2002) performed a genome scan in a large European family (pedigree Fr017) in which at least 20 members had autosomal dominant, adult-onset ALS unlinked to chromosome 21. They found linkage of the disorder in this family to chromosome 18q21 (maximum lod score of 4.5) within a 7.5-cM, 8-Mb region flanked by markers D18S846 and D18S1109. The authors stated that the familial ALS locus on chromosome 18 may represent a common form of familial ALS.
Associations Pending Confirmation
Among 376 individuals with sporadic ALS, Course et al. (2020) identified a 69-bp variable number tandem repeat (VNTR) in the last intron of the WDR7 gene (613473.0001) that was associated with the disease. The VNTR, which was initially found by long-read sequencing of genomes from over 100 patients with ALS, was located within the ALS3 locus on chromosome 18q21. Detailed analysis showed that the VNTR was highly variable in length and was longer in patients with sporadic ALS compared to controls. The repeats mostly ranged from 1 to 47; however, the longest repeat, which was 86 copies, was detected in a man who developed sporadic ALS at age 72 years. In the cohort, there was no relationship between length of the repeat and age at onset, and there was no evidence of genetic anticipation in a large multigenerational family with the repeat. The 69-bp repeat itself was found to vary at 6 nucleotides in the repeat unit; however, there was variability in the internal repeat sequence even in those who shared the same repeat length. Patterns were observed in the repeats, which suggested that the expansion occurs in combinations of 2 repeat units. Each unit has up to 21 nucleotides of self-complementary sequence. In vitro cellular expression studies in HEK293 cells demonstrated that the repeats could form microRNAs and cause RNA aggregation in the cytoplasm. Course et al. (2020) suggested that the pathogenic mechanism involves replication error due to template switching. Comparison with ancient genomes indicated that expansion of the WDR7 repeat predates modern humans.
Brown, R. H., Jr. Amyotrophic lateral sclerosis: recent insights from genetics and transgenic mice. Cell 80: 687-692, 1995. [PubMed: 7889564] [Full Text: https://doi.org/10.1016/0092-8674(95)90346-1]
Course, M. M., Gudsnuk, K., Smukowski, S. N., Winston, K., Desai, N., Ross, J. P., Sulovari, A., Bourassa, C. V., Spiegelman, D., Couthouis, J., Yu, C.-E., Tsuang, D. W., Jayadev, S., Kay, M. A., Gitler, A. D., Dupre, N., Eichler, E. E., Dion, P. A., Rouleau, G. A., Valdmanis, P. N. Evolution of a human-specific tandem repeat associated with ALS. Am. J. Hum. Genet. 107: 445-460, 2020. [PubMed: 32750315] [Full Text: https://doi.org/10.1016/j.ajhg.2020.07.004]
Hand, C. K., Khoris, J., Salachas, F., Gros-Louis, F., Simoes Lopes, A. A., Mayeux-Portas, V., Brewer, C. G., Brown, R. H., Jr., Meininger, V., Camu, W., Rouleau, G. A. A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. Am. J. Hum. Genet. 70: 251-256, 2002. Note: Erratum: Am. J. Hum. Genet. 71: 1007 only, 2002. [PubMed: 11706389] [Full Text: https://doi.org/10.1086/337945]