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Whole-blood dysregulation of actin-cytoskeleton pathway in adult spinal muscular atrophy patients.
Ann Clin Transl Neurol. 2020 Jul; 7(7):1158-1165.AC

Abstract

OBJECTIVE

Recent advances in therapeutics have improved prognosis for severely affected spinal muscular atrophy (SMA) type 1 and 2 patients, while the best method of treatment for SMA type 3 patients with later onset of disease is unknown. To better characterize the SMA type 3 population and provide potential therapeutic targets, we aimed to understand gene expression differences in whole blood of SMA type 3 patients (n = 31) and age- and gender-matched controls (n = 34).

METHODS

We performed the first large-scale whole blood transcriptomic screen with L1000, a rapid, high-throughput gene expression profiling technology that uses 978 landmark genes to capture a representation of the transcriptome and predict expression of 9196 additional genes.

RESULTS

The primary downregulated KEGG pathway in adult SMA type 3 patients was "Regulation of Actin Cytoskeleton," and downregulated expression of key genes in this pathway, including ROCK1, RHOA, and ACTB, was confirmed in the same whole blood samples using RT-qPCR. SMA type 3 patient-derived fibroblasts had lower expression of these genes compared to control fibroblasts from unaffected first-degree relatives. Overexpression of SMN levels using an AAV vector in fibroblasts did not normalize ROCK1, RHOA, and ACTB mRNA expression, indicating the involvement of additional genes in cytoskeleton dynamic regulation.

INTERPRETATION

Our findings from whole blood and patient-derived fibroblasts suggest SMA type 3 patients have decreased expression of actin cytoskeleton regulators. These observations provide new insights and potential therapeutic targets for SMA patients with longstanding denervation and secondary musculoskeletal pathophysiology.

Authors+Show Affiliations

Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA.Broad Institute of MIT and Harvard, Cambridge, MA, USA.Broad Institute of MIT and Harvard, Cambridge, MA, USA.Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.Broad Institute of MIT and Harvard, Cambridge, MA, USA.Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32558393

Citation

Siranosian, Jennifer J., et al. "Whole-blood Dysregulation of Actin-cytoskeleton Pathway in Adult Spinal Muscular Atrophy Patients." Annals of Clinical and Translational Neurology, vol. 7, no. 7, 2020, pp. 1158-1165.
Siranosian JJ, Nery FC, Alves CRR, et al. Whole-blood dysregulation of actin-cytoskeleton pathway in adult spinal muscular atrophy patients. Ann Clin Transl Neurol. 2020;7(7):1158-1165.
Siranosian, J. J., Nery, F. C., Alves, C. R. R., Siranosian, B. A., Lyons, N. J., Eichelberger, E. J., Garner, R., Da Silva Duarte Lepez, S., Johnstone, A. J., Subramanian, A., & Swoboda, K. J. (2020). Whole-blood dysregulation of actin-cytoskeleton pathway in adult spinal muscular atrophy patients. Annals of Clinical and Translational Neurology, 7(7), 1158-1165. https://doi.org/10.1002/acn3.51092
Siranosian JJ, et al. Whole-blood Dysregulation of Actin-cytoskeleton Pathway in Adult Spinal Muscular Atrophy Patients. Ann Clin Transl Neurol. 2020;7(7):1158-1165. PubMed PMID: 32558393.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Whole-blood dysregulation of actin-cytoskeleton pathway in adult spinal muscular atrophy patients. AU - Siranosian,Jennifer J, AU - Nery,Flavia C, AU - Alves,Christiano R R, AU - Siranosian,Benjamin A, AU - Lyons,Nicholas J, AU - Eichelberger,Eric J, AU - Garner,Reid, AU - Da Silva Duarte Lepez,Salomé, AU - Johnstone,Alec J, AU - Subramanian,Aravind, AU - Swoboda,Kathryn J, Y1 - 2020/06/17/ PY - 2020/03/10/received PY - 2020/05/09/revised PY - 2020/05/14/accepted PY - 2020/6/20/pubmed PY - 2020/6/20/medline PY - 2020/6/20/entrez SP - 1158 EP - 1165 JF - Annals of clinical and translational neurology JO - Ann Clin Transl Neurol VL - 7 IS - 7 N2 - OBJECTIVE: Recent advances in therapeutics have improved prognosis for severely affected spinal muscular atrophy (SMA) type 1 and 2 patients, while the best method of treatment for SMA type 3 patients with later onset of disease is unknown. To better characterize the SMA type 3 population and provide potential therapeutic targets, we aimed to understand gene expression differences in whole blood of SMA type 3 patients (n = 31) and age- and gender-matched controls (n = 34). METHODS: We performed the first large-scale whole blood transcriptomic screen with L1000, a rapid, high-throughput gene expression profiling technology that uses 978 landmark genes to capture a representation of the transcriptome and predict expression of 9196 additional genes. RESULTS: The primary downregulated KEGG pathway in adult SMA type 3 patients was "Regulation of Actin Cytoskeleton," and downregulated expression of key genes in this pathway, including ROCK1, RHOA, and ACTB, was confirmed in the same whole blood samples using RT-qPCR. SMA type 3 patient-derived fibroblasts had lower expression of these genes compared to control fibroblasts from unaffected first-degree relatives. Overexpression of SMN levels using an AAV vector in fibroblasts did not normalize ROCK1, RHOA, and ACTB mRNA expression, indicating the involvement of additional genes in cytoskeleton dynamic regulation. INTERPRETATION: Our findings from whole blood and patient-derived fibroblasts suggest SMA type 3 patients have decreased expression of actin cytoskeleton regulators. These observations provide new insights and potential therapeutic targets for SMA patients with longstanding denervation and secondary musculoskeletal pathophysiology. SN - 2328-9503 UR - https://www.unboundmedicine.com/medline/citation/32558393/Whole-blood_dysregulation_of_actin-cytoskeleton_pathway_in_adult_spinal_muscular_atrophy_patients L2 - https://doi.org/10.1002/acn3.51092 DB - PRIME DP - Unbound Medicine ER -
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