Abstract
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.
| Language | English |
|---|---|
| Pages | 304-312 |
| Number of pages | 9 |
| Journal | Neurodegenerative Diseases |
| Volume | 17 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 1 Dec 2017 |
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Keywords
- Amyotrophic lateral sclerosis
- Heterogeneous nuclear ribonucleoproteins
- Neurogenetics
- Neuropathology
Cite this
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Genetic and pathological assessment of hnRNPA1, hnRNPA2/B1, and hnRNPA3 in familial and sporadic amyotrophic lateral sclerosis. / Fifita, Jennifer A.; Zhang, Katharine Y.; Galper, Jasmin; Williams, Kelly L.; McCann, Emily P.; Hogan, Alison L.; Saunders, Neil; Bauer, Denis; Tarr, Ingrid S.; Pamphlett, Roger; Nicholson, Garth A.; Rowe, Dominic; Yang, Shu; Blair, Ian P.
In: Neurodegenerative Diseases, Vol. 17, No. 6, 01.12.2017, p. 304-312.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Genetic and pathological assessment of hnRNPA1, hnRNPA2/B1, and hnRNPA3 in familial and sporadic amyotrophic lateral sclerosis
AU - Fifita, Jennifer A.
AU - Zhang, Katharine Y.
AU - Galper, Jasmin
AU - Williams, Kelly L.
AU - McCann, Emily P.
AU - Hogan, Alison L.
AU - Saunders, Neil
AU - Bauer, Denis
AU - Tarr, Ingrid S.
AU - Pamphlett, Roger
AU - Nicholson, Garth A.
AU - Rowe, Dominic
AU - Yang, Shu
AU - Blair, Ian P.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
KW - Amyotrophic lateral sclerosis
KW - Heterogeneous nuclear ribonucleoproteins
KW - Neurogenetics
KW - Neuropathology
UR - http://www.scopus.com/inward/record.url?scp=85038902448&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/nhmrc/1095215
UR - http://purl.org/au-research/grants/nhmrc/1092023
U2 - 10.1159/000481258
DO - 10.1159/000481258
M3 - Article
VL - 17
SP - 304
EP - 312
JO - Neurodegenerative Diseases
T2 - Neurodegenerative Diseases
JF - Neurodegenerative Diseases
SN - 1660-2854
IS - 6
ER -