TY - JOUR
T1 - Channelopathy-related SCN10A gene variants predict cerebellar dysfunction in multiple sclerosis
AU - Roostaei, Tina
AU - Sadaghiani, Shokufeh
AU - Park, Min Tae M.
AU - Mashhadi, Rahil
AU - Nazeri, Aria
AU - Noshad, Sina
AU - Salehi, Mohammad Javad
AU - Naghibzadeh, Maryam
AU - Moghadasi, Abdorreza Naser
AU - Owji, Mahsa
AU - Doosti, Rozita
AU - Taheri, Amir Pejman Hashemi
AU - Rad, Ali Shakouri
AU - Azimi, Amirreza
AU - Chakravarty, M. Mallar
AU - Voineskos, Aristotle N.
AU - Nazeri, Arash
AU - Sahraian, Mohammad Ali
N1 - Funding Information:
The authors thank Professor Douglas Arnold, Dr. Sridar Narayanan, and Dr. Andre van der Kouwe for support and expert advice on MRI acquisition and study design; the study participants who contributed to this study; and their colleagues in the CRIMSON study group and the Multiple Sclerosis Research Center. This study was supported by Tehran University of Medical Sciences and the MS Society of Iran. The funding sources had no influence on the writing of the manuscript or the decision to submit it for publication. T.R. and Arash Nazeri were supported by a Jacqueline Du Pré grant provided by the Multiple Sclerosis International Federation (www.msif. org). Arash Nazeri is a recipient of the CAMH fellowship award. A.N.V. is funded by the Canadian Institutes of Health Research, Ontario Mental Health Foundation, NARSAD, and the National Institute of Mental Health (R01MH099167 and R01MH102324). M.M.C. is funded by the W. Garfield Weston Foundation and Natural Sciences and Engineering Research Council.
Publisher Copyright:
© 2016 American Academy of Neurology.
PY - 2016/2/2
Y1 - 2016/2/2
N2 - Objective: To determine the motor-behavioral and neural correlates of putative functional common variants in the sodium-channel NaV1.8 encoding gene (SCN10A) in vivo in patients with multiple sclerosis (MS). Methods: We recruited 161 patients with relapsing-onset MS and 94 demographically comparable healthy participants. All patients with MS underwent structural MRI and clinical examinations (Expanded Disability Status Scale [EDSS] and Multiple Sclerosis Functional Composite [MSFC]). Whole-brain voxel-wise and cerebellar volumetry were performed to assess differences in regional brain volumes between genotype groups. Resting-state fMRI was acquired from 62 patients with MS to evaluate differences in cerebellar functional connectivity. All participants were genotyped for 4 potentially functional SCN10A polymorphisms. Results: Two SCN10A polymorphisms in high linkage disequilibrium (r2 = 0.95) showed significant association with MSFC performance in patients with MS (rs6795970: p = 6.2 × 10-4; rs6801957: p = 0.0025). Patients with MS with rs6795970AA genotype performed significantly worse than rs6795970G carriers in MSFC (p = 1.8 × 10-4) and all of its subscores. This association was independent of EDSS and cerebellar atrophy. Although the genotype groups showed no difference in regional brain volumes, rs6795970AA carriers demonstrated significantly diminished cerebellar functional connectivity with the thalami and midbrain. No significant SCN10A-genotype effect was observed on MSFC performance in healthy participants. Conclusions: Our data suggest that SCN10A variation substantially influences functional status, including prominent effects on motor coordination in patients with MS. These findings were supported by the effects of this variant on a neural system important for motor coordination, namely cerebello-thalamic circuitry. Overall, our findings add to the emerging evidence that suggests that sodium channel NaV1.8 could serve as a target for future drug-based interventions to treat cerebellar dysfunction in MS.
AB - Objective: To determine the motor-behavioral and neural correlates of putative functional common variants in the sodium-channel NaV1.8 encoding gene (SCN10A) in vivo in patients with multiple sclerosis (MS). Methods: We recruited 161 patients with relapsing-onset MS and 94 demographically comparable healthy participants. All patients with MS underwent structural MRI and clinical examinations (Expanded Disability Status Scale [EDSS] and Multiple Sclerosis Functional Composite [MSFC]). Whole-brain voxel-wise and cerebellar volumetry were performed to assess differences in regional brain volumes between genotype groups. Resting-state fMRI was acquired from 62 patients with MS to evaluate differences in cerebellar functional connectivity. All participants were genotyped for 4 potentially functional SCN10A polymorphisms. Results: Two SCN10A polymorphisms in high linkage disequilibrium (r2 = 0.95) showed significant association with MSFC performance in patients with MS (rs6795970: p = 6.2 × 10-4; rs6801957: p = 0.0025). Patients with MS with rs6795970AA genotype performed significantly worse than rs6795970G carriers in MSFC (p = 1.8 × 10-4) and all of its subscores. This association was independent of EDSS and cerebellar atrophy. Although the genotype groups showed no difference in regional brain volumes, rs6795970AA carriers demonstrated significantly diminished cerebellar functional connectivity with the thalami and midbrain. No significant SCN10A-genotype effect was observed on MSFC performance in healthy participants. Conclusions: Our data suggest that SCN10A variation substantially influences functional status, including prominent effects on motor coordination in patients with MS. These findings were supported by the effects of this variant on a neural system important for motor coordination, namely cerebello-thalamic circuitry. Overall, our findings add to the emerging evidence that suggests that sodium channel NaV1.8 could serve as a target for future drug-based interventions to treat cerebellar dysfunction in MS.
UR - http://www.scopus.com/inward/record.url?scp=84957548786&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000002326
DO - 10.1212/WNL.0000000000002326
M3 - Article
C2 - 26740675
AN - SCOPUS:84957548786
SN - 0028-3878
VL - 86
SP - 410
EP - 417
JO - Neurology
JF - Neurology
IS - 5
ER -