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Karger Publishers, Neurodegenerative Diseases, 6(17), p. 304-312, 2017

DOI: 10.1159/000481258

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Genetic and Pathological Assessment of hnRNPA1, hnRNPA2/B1, and hnRNPA3 in Familial and Sporadic Amyotrophic Lateral Sclerosis

This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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Abstract

<b><i>Background:</i></b> 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. <b><i>Objective:</i></b> To further assess their role in ALS, we examined these hnRNPs in spinal cord tissue from sporadic (SALS) and familial ALS (FALS) patients, including <i>C9orf72</i> repeat expansion-positive patients, and controls. We also sought to determine the prevalence of <i>HNRNPA1</i>, <i>HNRNPA2B1,</i> and <i>HNRNPA3</i> mutations in Australian ALS patients. <b><i>Methods:</i></b> Immunostaining was used to assess hnRNPs in ALS patient spinal cords. Mutation analysis of the <i>HNRNPA1</i>, <i>HNRNPA2B1,</i> and <i>HNRNPA3 </i>genes was performed in FALS and of their prion-like domains in SALS patients. <b><i>Results:</i></b> Immunostaining of spinal motor neurons of ALS patients with the <i>C9orf72</i> 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 <i>HNRNPA1</i>, <i>HNRNPA2B1,</i> or <i>HNRNPA3</i> in Australian ALS patients. <b><i>Conclusions:</i></b> hnRNPA3 pathology was identified in motor neurons of ALS patients with<i> C9orf72</i> repeat expansions, implicating hnRNPA3 in the pathogenesis of <i>C9orf72</i>-linked ALS. hnRNPA3 warrants further investigation into the pathogenesis of ALS linked to <i>C9orf72</i>. This study also determined that <i>HNRNP</i> mutations are not a common cause of FALS and SALS in Australia.