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

*Corresponding author for this work

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    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.

    Original languageEnglish
    Article number386
    Number of pages8
    JournalNeurology. Genetics
    Volume6
    Issue number1
    DOIs
    Publication statusPublished - Feb-2020

    Keywords

    • MOTOR-NEURON PROTEIN
    • PLASTIN 3 EXPRESSION
    • SMN PROTEIN
    • MUTATIONS
    • GENE
    • IDENTIFICATION

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