TY - JOUR
T1 - Analysis of FUS, PFN2, TDP-43, and PLS3 as potential disease severity modifiers in spinal muscular atrophy
AU - Wadman, Renske I
AU - Jansen, Marc D
AU - Curial, Chantall A D
AU - Groen, Ewout J N
AU - Stam, Marloes
AU - Wijngaarde, Camiel A
AU - Medic, Jelena
AU - Sodaar, Peter
AU - van Eijk, Kristel R
AU - Huibers, Manon M H
AU - van Kuik, Joyce
AU - Lemmink, Henny H
AU - van Rheenen, Wouter
AU - Veldink, Jan Herman
AU - van den Berg, Leonard H
AU - van der Pol, W Ludo
N1 - Funding Information:
The Article Processing Charge was funded by the authors.
Publisher Copyright:
© American Academy of Neurology.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/2
Y1 - 2020/2
N2 - Objective: To investigate mutations in genes that are potential modifiers of spinal muscular atrophy (SMA) severity.Methods: We performed a hypothesis-based search into the presence of variants in fused in sarcoma (FUS), transactive response DNA-binding protein 43 (TDP-43), plastin 3 (PLS3), and profilin 2 (PFN2) in a cohort of 153 patients with SMA types 1-4, including 19 families. Variants were detected with targeted next-generation sequencing and confirmed with Sanger sequencing. Functional effects of the identified variants were analyzed in silico and for PLS3, by analyzing expression levels in peripheral blood.Results: We identified 2 exonic variants in FUS exons 5 and 6 (p.R216C and p.S135N) in 2 unrelated patients, but clinical effects were not evident. We identified 8 intronic variants in PLS3 in 33 patients. Five PLS3 variants (c.1511+82T>C; c.748+130 G>A; c.367+182C>T; c.891-25T>C (rs145269469); c.1355+17A>G (rs150802596)) potentially alter exonic splice silencer or exonic splice enhancer sites. The variant c.367+182C>T, but not RNA expression levels, corresponded with a more severe phenotype in 1 family. However, this variant or level of PLS3 expression did not consistently correspond with a milder or more severe phenotype in other families or the overall cohort. We found 3 heterozygous, intronic variants in PFN2 and TDP-43 with no correlation with clinical phenotype or effects on splicing.Conclusions: PLS3 and FUS sequence variants do not modify SMA severity at the population level. Specific variants in individual patients or families do not consistently correlate with disease severity.
AB - Objective: To investigate mutations in genes that are potential modifiers of spinal muscular atrophy (SMA) severity.Methods: We performed a hypothesis-based search into the presence of variants in fused in sarcoma (FUS), transactive response DNA-binding protein 43 (TDP-43), plastin 3 (PLS3), and profilin 2 (PFN2) in a cohort of 153 patients with SMA types 1-4, including 19 families. Variants were detected with targeted next-generation sequencing and confirmed with Sanger sequencing. Functional effects of the identified variants were analyzed in silico and for PLS3, by analyzing expression levels in peripheral blood.Results: We identified 2 exonic variants in FUS exons 5 and 6 (p.R216C and p.S135N) in 2 unrelated patients, but clinical effects were not evident. We identified 8 intronic variants in PLS3 in 33 patients. Five PLS3 variants (c.1511+82T>C; c.748+130 G>A; c.367+182C>T; c.891-25T>C (rs145269469); c.1355+17A>G (rs150802596)) potentially alter exonic splice silencer or exonic splice enhancer sites. The variant c.367+182C>T, but not RNA expression levels, corresponded with a more severe phenotype in 1 family. However, this variant or level of PLS3 expression did not consistently correspond with a milder or more severe phenotype in other families or the overall cohort. We found 3 heterozygous, intronic variants in PFN2 and TDP-43 with no correlation with clinical phenotype or effects on splicing.Conclusions: PLS3 and FUS sequence variants do not modify SMA severity at the population level. Specific variants in individual patients or families do not consistently correlate with disease severity.
UR - http://www.scopus.com/inward/record.url?scp=85081920245&partnerID=8YFLogxK
U2 - 10.1212/NXG.0000000000000386
DO - 10.1212/NXG.0000000000000386
M3 - Article
C2 - 32042914
SN - 2376-7839
VL - 6
SP - 1
EP - 9
JO - Neurology. Genetics
JF - Neurology. Genetics
IS - 1
M1 - e386
ER -