This report describes amyotrophic lateral sclerosis 18 (ALS18), which is a subtype of amyotrophic lateral sclerosis; ALS18 exhibits autosomal dominant inheritance. The human gene implicated in this disease is profilin 1 (PFN1), which encodes an actin-monomer-binding protein. There are four profilin genes in human, PFN1, PFN2, PFN3, and PFN4; chic is the only profilin gene in flies. Classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for chic.
Multiple UAS constructs of human Hsap\PFN1 have been introduced into flies, including wild-type PFN1 and genes carrying variants implicated in ALS18. Partial heterologous rescue (functional complementation) has been observed: expression of either wild-type or mutant Hsap\PFN1 in glutamatergic neurons is sufficient to rescue the pupal lethality resulting from RNAi-effected loss of chic expression using the same GAL4 driver.
Variant(s) implicated in human disease tested (as transgenic human gene, PFN1): the C71G and M114T variant forms have been introduced into flies. Expression of human PFN1 in glutamatergic neurons results in progressive locomotion defects and shorter lifespan in adult flies; ALS-implicated PFN1 mutants display a less toxic effect. Expression in other neural tissues, such as the eye, has little or no effect.
Animals homozygous for amorphic mutations of chic die during the embryonic stage; mutant embryos exhibit developmental and neuroanatomy defects. Phenotypes in the adult brain and other late stages have been characterized using somatic clones. Muscle-specific overexpression results in elongated sarcomeres, myofibrillar disorganization, and sarcomeric disarray; these cellular phenotypes correlate with phenotypes of impaired muscle function (flight and climbing in adults). Extensive genetic and physical interactions have been described for Dmel\chic; see below and in the chic gene report.
See also the human disease model report 'cardiomyopathy, hypertrophic (postulated), profilin-related' (FBhh0000705).
[updated Apr. 2018 by FlyBase; FBrf0222196]
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996, pubmed:8875253). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. [from MIM:105400, 2015.02.11]
[AMYOTROPHIC LATERAL SCLEROSIS 18; ALS18](https://omim.org/entry/614808)
[PROFILIN 1; PFN1](https://omim.org/entry/176610)
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, it was 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. (Wu et al.,2012, pubmed:22801503) [from MIM:614808, 2015.02.12]
ALS18 is caused by heterozygous mutation in the PFN1 gene. [from MIM:614808, 2015.02.12]
In vitro assays showed that ALS-associated mutant PFN1 produces ubiquitinated, insoluble aggregates in transfected cells. In many cases the aggregates contained the ALS-associated protein TDP43 (TARDBP). The E117G mutation displayed a distribution more similar to that of wildtype PFN1, with most of the expressed protein in the soluble fraction. [In transfected cultured primary motor neurons] mutant PFN1 inhibited axon outgrowth. These results indicated that mutations in the PFN1 gene account for approximately 1 to 2% of familial ALS and suggested that disruption of cytoskeletal pathways contribute importantly to ALS pathogenicity (Wu et al., 2012, pubmed:22801503). [from MIM:176610, 2015.02.12]
Profilin-1 is a 140-amino acid protein and major growth regulator of filamentous (F)-actin through its binding of monomeric (G)-actin. (Mockrin and Korn, 1980, pubmed:6893804). [from MIM:176610, 2015.02.12]
Many to one: 3 profilin genes in human, PFN4, PFN1, and PFN2 show similarity to the single Drosophila profilin, chic.
Low- to moderate-scoring ortholog of human PFN4, PFN1, and PFN2; Dmel\chic shares 28% identity and 42% similarity with PFN1 and PFN4.
