Genetic and pathological assessment of hnRNPA1, hnRNPA2/B1, and hnRNPA3 in familial and sporadic amyotrophic lateral sclerosis

Jennifer A. Fifita, Katharine Y. Zhang, Jasmin Galper, Kelly L. Williams, Emily P. McCann, Alison L. Hogan, Neil Saunders, Denis Bauer, Ingrid S. Tarr, Roger Pamphlett, Garth A. Nicholson, Dominic Rowe, Shu Yang, Ian P. Blair

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


Background: Mutations in the genes encoding the heterogeneous nuclear ribonucleoproteins hnRNPA1 and hnRNPA2/B1 have been reported in a multisystem proteinopathy that includes amyotrophic lateral sclerosis (ALS) and inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia. Mutations were also described in the prion-like domain of hnRNPA1 in patients with classic ALS. Another hnRNP protein, hnRNPA3, has been found to be associated with the ALS/frontotemporal dementia protein C9orf72. Objective: To further assess their role in ALS, we examined these hnRNPs in spinal cord tissue from sporadic (SALS) and familial ALS (FALS) patients, including C9orf72 repeat expansion-positive patients, and controls. We also sought to determine the prevalence of HNRNPA1, HNRNPA2B1, and HNRNPA3 mutations in Australian ALS patients. Methods: Immunostaining was used to assess hnRNPs in ALS patient spinal cords. Mutation analysis of the HNRNPA1, HNRNPA2B1, and HNRNPA3 genes was performed in FALS and of their prion-like domains in SALS patients. Results: Immunostaining of spinal motor neurons of ALS patients with the C9orf72 repeat expansion showed significant mislocalisation of hnRNPA3, and no differences in hnRNPA1 or A2/B1 localisation, compared to controls. No novel or known mutations were identified in HNRNPA1, HNRNPA2B1, or HNRNPA3 in Australian ALS patients. Conclusions: hnRNPA3 pathology was identified in motor neurons of ALS patients with C9orf72 repeat expansions, implicating hnRNPA3 in the pathogenesis of C9orf72-linked ALS. hnRNPA3 warrants further investigation into the pathogenesis of ALS linked to C9orf72. This study also determined that HNRNP mutations are not a common cause of FALS and SALS in Australia.

Original languageEnglish
Pages (from-to)304-312
Number of pages9
JournalNeurodegenerative Diseases
Issue number6
Publication statusPublished - 1 Dec 2017


  • Amyotrophic lateral sclerosis
  • Heterogeneous nuclear ribonucleoproteins
  • Neurogenetics
  • Neuropathology


Dive into the research topics of 'Genetic and pathological assessment of hnRNPA1, hnRNPA2/B1, and hnRNPA3 in familial and sporadic amyotrophic lateral sclerosis'. Together they form a unique fingerprint.

Cite this