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]