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FB2026_01
,
released March 12, 2026
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, MIM: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.
The human HNRNPA1 gene has also been associated with the disease inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3 (IBMPFD3, MIM:615424, FBhh0000299). Some medical researchers now human describe IBMPFD3 and ALS20 as a single disease, multisystem proteinopathy 3 (MSP-3), with a continuum of symptoms. An orthologous gene in human, HNRNPA2B1, is implicated in inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 2 (IBMPFD2, aka MSP-2); see FBhh0000298.
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 Jul. 2021 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 20; ALS20](https://omim.org/entry/615426)
[HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A1; HNRNPA1](https://omim.org/entry/164017)
ALS20 is caused by heterozygous mutation in the HNRNPA1 gene. [from MIM:615426, 2015.04.22]
Muscle biopsies from an affected patient showed nuclear clearance and cytoplasmic inclusions of HNRNPA1 protein in 10% of muscle fibres.
Disease-associated mutations are localized to the prion-like domains (PrLD) of HNRNPA1 and HNRNPA2B1. In vitro, disease-associated mutations greatly accelerate HNRNPA1 and HNRNPA2B1 fibrillization, and directly promote nucleation of wild-type HNRNPA1 and HNRNPA2B1 into fibrils.
A recent emerging theme in ALS research is the hypothesis that some ALS-associated proteins have a key role in the formation and function of cytoplasmic RNP stress granules, a cytosolic component in which non-functional translation initiation products accumulate. Stress granules form in response to a number of environmental stresses known to impede translation of mRNA into protein. Several ALS-associated proteins that have prion-like domains have been identified as accumulating in stress granules, including HNRNPA1.
Kim et al., 2013, (pubmed:23455423) reported that HNRNPA1 has a C-terminal glycine-rich domain that is essential for activity and mediates interaction with TARDBP, the protein associated with ALS10. This low-complexity domain is predicted to be intrinsically unfolded and has an amino acid composition similar to that of yeast prion domains. Approximately 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a similar distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. Kim et al., 2013, (pubmed:23455423) showed that HNRNPA1 has an intrinsic tendency to assemble into self-seeding fibrils. Kim et al., 2013, (pubmed:23455423) screened 212 familial ALS cases for sequence variants in the HNRNPA2B1 or HNRNPA1 genes. They identified 1 dominantly inherited case in which known ALS genes had been excluded with mutation in the HNRNPA1 gene. Kim et al., 2013, (pubmed:23455423) also screened 305 sporadic ALS cases and identified a nonsynonymous HNRNPA1 variant in an individual with classic, late-onset ALS [from MIM:164017, 2015.04.22]
Many to many: 5 human to 4 Drosophila.
Ortholog of human HNRNPA2B1, HNRNPA3, HNRNPA1, HNRNPA1L2, and HNRNPA0 (4 Drosophila to 5 human; additional more distantly related gene(s) in both species). Dmel\Hrb98DE shares 50% identity and 64% similarity with human HNRNPA2B1, 50% identity and 62% similarity with human HNRNPA3, 49% identity and 63% similarity with human HNRNPA1L2, 48% identity and 64% similarity with human HNRNPA1, and 44% identity and 59% similarity with human HNRNPA0.