Whole-exome sequencing identifies a missense mutation in hnRNPA1 in a family with flail arm ALS

Abstract

Our results suggest that hnRNPA1 is the causative gene in the family with flail arm ALS. This further expanded the disease phenotype of hnRNPA1 mutations.

Decoding ALS: from genes to mechanism

“…The importance of TDP-43 in pathogenesis was cemented by the identification of ALS-causing mutations in this RNA-binding protein 69 . The subsequent identification of ALS-causing mutations in related RNA-binding proteins, including FUS and hnRNPA1, focused substantial attention on the role of RNA biology in pathogenesis 70–73 (Fig. 2f).…”

“…It should be noted that some disease-causing mutations in RNA-binding proteins do not impact the LCD. For example, some ALS-causing mutations in FUS and hnRNPA1 disturb the nuclear localization sequence (NLS) and result in accumulation of these proteins in the cytoplasm 70,71,73 . Phase transition by LCD-containing RNA-binding proteins is exquisitely concentration dependent 82 , and it is likely that increased accumulation of FUS and hnRNPA1 in the cytoplasm as a consequence of mutations impacting their respective NLSs is sufficient to drive excess phase separation, as evidenced by hyperassembly of stress granules in cells derived from patients with the respective mutations 72,87 .…”

Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases

“…Insight into a potential common pathway has recently been highlighted by a series of studies that have implicated defects in nucleocytoplasmic transport as a shared consequence downstream of a variety of ALS-initiating mutations. These include the identification of ALS-causing mutations in the nuclear localization signals (NLSs) of FUS and hnRNPA1 (Dormann et al, 2010; Gal et al, 2011; Liu et al, 2016), evidence of impaired nucleocytoplasmic transport downstream of C9ORF72 -related ALS-FTD (Boeynaems et al, 2016; Freibaum et al, 2015; Jovičić et al, 2015; Shi et al, 2017; Zhang et al, 2015), and recognition that cytoplasmic protein aggregates of TDP-43, and cytoplasmic deposition of amyloids more generally, interfere with nucleocytoplasmic transport of protein and RNA (Woerner et al, 2016). In this review, we provide an overview of the current understanding of nucleocytoplasmic transport through the nuclear pore complex (NPC) in mammalian cells.…”

“…For example, one patient with a C-terminal truncation mutation that entirely removed the NLS in FUS showed dramatic redistribution of FUS into the cytoplasm and very early age of onset (DeJesus-Hernandez et al, 2010). More recently, a novel missense mutation in the NLS of hnRNPA1, which causes redistribution of hnRNPA1 from the nucleus to the cytoplasm, was identified as a cause of familial ALS (Liu et al, 2016), expanding the repertoire of NLS mutations in ALS-associated proteins. Interestingly, mutations that disrupt the NLS in a related protein, hnRNPH2, cause neurodevelopmental delay and autism (Bain et al, 2016).…”

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

“…However, about 5%-10% of ALS cases have a family history of the disorder, typically with dominant inheritance. During the past decades, pathogenic mutations in a number of genes, including ORF 72 on chromosome 9 (C9orf72), superoxide dismutase 1 (SOD1), TAR DNA binding protein (TARDBP, also known as TDP- 43), FUS RNA binding protein (FUS), heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), sequestosome 1 (SQSTM1), valosin-containing protein (VCP), optineurin (OPTN), TANK binding kinase 1 (TBK1), ubiquilin 2 (UBQLN2), and profilin 1 (PFN1), have been identified in ALS (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). These genes are involved in a variety of cellular pathways, including protein homeostasis, RNA metabolism, and cytoskeletal dynamics.…”