# 614808
AMYOTROPHIC LATERAL SCLEROSIS 18; ALS18
ORPHA: 803; DO: 0060209;
Phenotype-Gene Relationships
| Location | Phenotype | Phenotype MIM number |
Inheritance | Phenotype mapping key |
Gene/Locus | Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17p13.2 | Amyotrophic lateral sclerosis 18 | 614808 | 3 | PFN1 | 176610 |
TEXT
A number sign (#) is used with this entry because amyotrophic lateral sclerosis-18 (ALS18) is caused by heterozygous mutation in the PFN1 gene (176610) on chromosome 17p.
For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
Clinical Features
Among 22 cases of ALS that resulted from mutations in PFN1 (ALS18), all displayed limb onset. Given that bulbar onset represents approximately 25% of ALS cases, Wu et al. (2012) proposed that their observation suggests a common clinical phenotype among patients with PFN1 mutations. The age of onset for familial ALS18 cases was 44.8 +/- 7.4 years.
Mapping
Wu et al. (2012) performed exome capture followed by deep sequencing on 2 large ALS families of Caucasian (family 1) and Sephardic Jewish (family 2) origin. Both displayed a dominant inheritance mode and were negative for known ALS-causing mutations. For each family, 2 affected members with maximum genetic distance were selected for exome sequencing. More than 150X coverage was achieved. Using a variety of filters, Wu et al. (2012) were able to reduce the number of candidate mutations to 2 within family 1 and 3 within family 2.
Molecular Genetics
Wu et al. (2012) identified 4 different missense mutations in 7 families segregating autosomal dominant ALS. Sequencing of the PFN coding region in 816 sporadic ALS samples identified 2 samples containing the E117G mutation (176610.0004). In each of the mutations, the altered amino acid was evolutionarily conserved down to the level of zebrafish.
REFERENCES
-
Wu, C.-H., Fallini, C., Ticozzi, N., Keagle, P. J., Sapp, P. C., Piotrowska, K., Lowe, P., Koppers, M., McKenna-Yasek, D., Baron, D. M., Kost, J. E., Gonzalez-Perez, P., and 26 others. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488: 499-503, 2012. [PubMed: 22801503] [Full Text: https://dx.doi.org/10.1038/nature11280]