Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the degeneration of the second motor-neuron. The phenotype ranges from very severe to very mild forms. All patients have the homozygous loss of the SMN1 gene and a variable number of SMN2 (generally two-to-four copies), inversely related with the severity. The amazing results of the available treatments have made compelling the need of prognostic biomarkers to predict the progression trajectories of patients. Beside the SMN2 products, few other biomarkers have been evaluated so far, including some miRs.
We performed whole miRNome analysis of muscle samples of patients and controls (14 biopsies and 9 cultures). The levels of miRs differentially expressed in muscle were evaluated in serum samples (51 patients and 37 controls) and integrated with SMN2 copies, SMN2-full length transcript levels in blood and age (SMA-score).
Over 100 miRs were differentially expressed in SMA muscle; three of them (HSA-miR-181a-5p, -324-5p, -451a; SMA-miRs) were significantly up-regulated in serum of patients. The severity predicted by the SMA-score was related with that of the clinical classification at a correlation coefficient of 0.87 (p<10-5).
miRNome analyses suggest the primary involvement of skeletal muscle in SMA pathogenesis. The SMA-miRs are likely actively released in the blood flow; their function and target cells require to be elucidated. The accuracy of the SMA-score needs to be verified in replicative studies: if confirmed, it could be crucial for the routine prognostic assessment, also in pre-symptomatic patients.
Telethon Italia (grant # GGP12116).
All data generated or analysed during this study are included in the manuscript and supporting files. Raw sequencing data are available at NCBI-SRA database; BioProject PRJNA748014
- Francesco Danilo Tiziano
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: According to the ARRIVE guidelines, procedures were carried out to minimize discomfort and pain, in compliance with National (D.L. 116 Suppl 40/1992 and D.L. 26/2014) and International guidelines and laws (2010/63/EU Legislation for the protection of animals used for scientific purposes). The experimental protocols were approved by the Ethics Committee of the Fondazione IRCCS Istituto Neurologico C. Besta and by the Italian Ministry of Health (protocol numbers: 962/2016-PR and 1039/2020-PR).
Human subjects: Informed consent was obtained from patients for genetic analyses. The study was approved by the local Ethics Committee
- Christopher Cardozo
© 2021, Abiusi et al.
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