Analysis of FUS, PFN2, TDP-43, and PLS3 as potential disease severity modifiers in spinal muscular atrophy

Renske I Wadman; Marc D Jansen; Chantall A D Curial; Ewout J N Groen; Marloes Stam; Camiel A Wijngaarde; Jelena Medic; Peter Sodaar; Kristel R van Eijk; Manon M H Huibers; Joyce van Kuik; Henny H Lemmink; Wouter van Rheenen; Jan Herman Veldink; Leonard H van den Berg; W Ludo van der Pol

doi:10.1212/NXG.0000000000000386

Analysis of FUS, PFN2, TDP-43, and PLS3 as potential disease severity modifiers in spinal muscular atrophy

Neurol Genet. 2019 Jan 3;6(1):e386. doi: 10.1212/NXG.0000000000000386. eCollection 2020 Feb.

Authors

Renske I Wadman¹, Marc D Jansen¹, Chantall A D Curial¹, Ewout J N Groen¹, Marloes Stam¹, Camiel A Wijngaarde¹, Jelena Medic¹, Peter Sodaar¹, Kristel R van Eijk¹, Manon M H Huibers¹, Joyce van Kuik¹, Henny H Lemmink¹, Wouter van Rheenen¹, Jan Herman Veldink¹, Leonard H van den Berg¹, W Ludo van der Pol¹

Affiliation

¹ Department of Neurology (R.I.W., M.D.J., C.A.D.C., E.J.N.G., M.S., C.A.W., J.M., P.S., K.R.E., W.R., J.H.V., L.H.B., W.L.P.), Brain Center Rudolf Magnus, University Medical Center Utrecht; Department of Pathology (M.M.H.H., J.K.), University Medical Center Utrecht; Department of Genetics (M.M.H.H.), University Medical Center Utrecht; and Department of Genetics (H.H.L.), University Medical Center Groningen, The Netherlands.

Abstract

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.