This report describes amyotrophic lateral sclerosis 20 (ALS20), which is a subtype of amyotrophic lateral sclerosis; ALS20 exhibits autosomal dominant inheritance. The human gene implicated in this disease is HNRNPA1, which encodes heterogeneous nuclear ribonucleoprotein A1. This gene has also been associated with the disease inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3 (IBMPFD3, OMIM:615424, FBhh0000299). There are two high-scoring fly orthologs: Hrb98DE, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated; and Hrb87F, for which RNAi targeting constructs and classical amorphic alleles have been generated. Only Hrb98DE has been analyzed in the context of ALS20/IBMPFD3 in flies. An orthologous gene in human, HNRNPA2B1, is implicated in inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 2 (IBMPFD2); see FBhh0000298.
A variant(s) implicated in IBMPFD3 (corresponds to D262V/D314V in the human HNRNPA1 gene) has been tested in flies, but no variants implicated in ALS20.
Multiple UAS constructs of the human Hsap\HNRNPA1 gene have been introduced into flies, including wild-type HNRNPA1 and a gene carrying a mutational lesion implicated in IBMPFD3. Transgenic expression of mutant constructs recapitulates some of the key phenotypes of ALS20 and IBMPFD, including degeneration of muscle fibers and the formation of cytoplasmic inclusions of mutant protein. Heterologous rescue of mutations in the Drosophila ortholog by expression of HNRNPA1 has not been tested
A UAS construct of Dmel\Hrb98DE bearing a mutation that corresponds to both the mutational lesion in HNRNPA1 that is implicated in IBMPFD3 and the mutational lesion in HNRNPA2B1 that is implicated in IBMPFD2 has been introduced into flies; it recapitulates some of the key phenotypes of ALS20 and IBMPFD, including degeneration of muscle fibers and the formation of cytoplasmic inclusions of mutant protein.
[updated Aug. 2019 by FlyBase; FBrf0222196]