Impact of a frequent nearsplice SOD1 variant in amyotrophic lateral sclerosis: optimising SOD1 genetic screening for gene therapy opportunities

Objective Mutations in superoxide dismutase 1 gene (SOD1), encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in SOD1 non-coding sequences, is pathogenic. Methods We analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases. Results We identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358–10T>G nearsplice SOD1 variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation. Conclusions Our results highlighted nearsplice/intronic mutations in SOD1 are responsible for a significant portion of French fALS and suggested the systematic analysis of the SOD1 mRNA sequence could become the method of choice for SOD1 screening, not to miss these specific cases.

[1]  Yipeng Zhao,et al.  A novel nonsense SOD1 mutation (p.Asn140Ter) in a sporadic amyotrophic lateral sclerosis case with rapid progression , 2021, Amyotrophic lateral sclerosis & frontotemporal degeneration.

[2]  M. Wilkerson,et al.  Identification of a pathogenic intronic KIF5A mutation in an ALS-FTD kindred , 2020, Neurology.

[3]  Timothy A. Miller,et al.  Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. , 2020, The New England journal of medicine.

[4]  Derek H. Oakley,et al.  SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS. , 2020, The New England journal of medicine.

[5]  M. Amador,et al.  Spastic paraplegia due to recessive or dominant mutations in ERLIN2 can convert to ALS , 2019, Neurology: Genetics.

[6]  E. Boltshauser,et al.  SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis. , 2019, Brain : a journal of neurology.

[7]  P. Andersen,et al.  Phenotype in an Infant with SOD1 Homozygous Truncating Mutation. , 2019, The New England journal of medicine.

[8]  Ciftci Vildan,et al.  Genetic alterations of C9orf72, SOD1, TARDBP, FUS, and UBQLN2 genes in patients with Amyotrophic Lateral Sclerosis , 2019, Cogent Medicine.

[9]  P. Andersen,et al.  A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient: insights into the underlying pathomechanisms , 2018, Neurobiology of Aging.

[10]  B. Pakkenberg,et al.  Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis , 2018, Acta Neuropathologica.

[11]  Gene W. Yeo,et al.  Genetic mutations in RNA-binding proteins and their roles in ALS , 2017, Human Genetics.

[12]  P. Klivényi,et al.  Genetic analysis of the SOD1 and C9ORF72 genes in Hungarian patients with amyotrophic lateral sclerosis , 2017, Neurobiology of Aging.

[13]  Zhi-rui Zhou,et al.  Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis , 2017, Journal of Neurology, Neurosurgery & Psychiatry.

[14]  Zhongsheng Sun,et al.  A novel 10-base pair insertion mutation in exon 5 of the SOD1 gene in a Chinese family with amyotrophic lateral sclerosis , 2016, Neurobiology of Aging.

[15]  E. Fisher,et al.  SOD1 Function and Its Implications for Amyotrophic Lateral Sclerosis Pathology , 2015, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[16]  Kevin F. Bieniek,et al.  A truncating SOD1 mutation, p.Gly141X, is associated with clinical and pathologic heterogeneity, including frontotemporal lobar degeneration , 2015, Acta Neuropathologica.

[17]  A. Nakamura,et al.  Slowly progressing lower motor neuron disease caused by a novel duplication mutation in exon 1 of the SOD1 gene , 2014, Neurobiology of Aging.

[18]  Lorne Zinman,et al.  Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis , 2014, Nature Neuroscience.

[19]  A. Al-Chalabi,et al.  The epidemiology of ALS: a conspiracy of genes, environment and time , 2013, Nature Reviews Neurology.

[20]  D. Shi,et al.  Identification of a novel Cys146X mutation of SOD1 in familial amyotrophic lateral sclerosis by whole-exome sequencing , 2012, Genetics in Medicine.

[21]  V. Meininger,et al.  Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes , 2012, Journal of Medical Genetics.

[22]  T. Mullen,et al.  SOD1, ANG, TARDBP and FUS mutations in amyotrophic lateral sclerosis: A United States clinical testing lab experience , 2012, Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.

[23]  B. Ni,et al.  A novel SOD1 mutation in amyotrophic lateral sclerosis with a distinct clinical phenotype , 2012, Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.

[24]  P. Andersen,et al.  ALS patients with SOD1 mutations in Switzerland show very diverse phenotypes and extremely long survival , 2011, Journal of Neurology, Neurosurgery & Psychiatry.

[25]  P. Andersen,et al.  A novel SOD1 splice site mutation associated with familial ALS revealed by SOD activity analysis. , 2010, Human molecular genetics.

[26]  G. Rouleau,et al.  A Mutation that Creates a Pseudoexon in SOD1 Causes Familial ALS , 2009, Annals of human genetics.

[27]  L. Hurst,et al.  Noisy splicing, more than expression regulation, explains why some exons are subject to nonsense-mediated mRNA decay , 2009, BMC Biology.

[28]  C. Béroud,et al.  Human Splicing Finder: an online bioinformatics tool to predict splicing signals , 2009, Nucleic acids research.

[29]  M. Morita,et al.  [Familial amyotrophic lateral sclerosis (FALS) with a novel SOD1 gene mutation: a clinicopathological study]. , 2007, Rinsho shinkeigaku = Clinical neurology.

[30]  A. Kakita,et al.  TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation , 2007, Acta Neuropathologica.

[31]  L. Mazzini,et al.  SOD1 gene mutations in Italian patients with Sporadic Amyotrophic Lateral Sclerosis (ALS) , 2006, Neuromuscular Disorders.

[32]  Bruce L. Miller,et al.  Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis , 2006, Science.

[33]  T. Siddique,et al.  Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[34]  A. Quattrone,et al.  Abnormally high levels of SOD1 mRNA in a patient with amyotrophic lateral sclerosis , 2004, Muscle & nerve.

[35]  Robert H. Brown,et al.  Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes. , 2003, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[36]  Christopher B. Burge,et al.  Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals , 2003, RECOMB '03.

[37]  Orla Hardiman,et al.  “True” sporadic ALS associated with a novel SOD‐1 mutation , 2002, Annals of neurology.

[38]  S. Salzberg,et al.  GeneSplicer: a new computational method for splice site prediction. , 2001, Nucleic acids research.

[39]  G. Rouleau,et al.  Compound heterozygous D90A and D96N SOD1 mutations in a recessive amyotrophic lateral sclerosis family , 2001, Annals of neurology.

[40]  Kenji Nakashima,et al.  New consensus research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 (SOD1) gene mutations: Inclusions containing SOD1 in neurons and astrocytes , 2000, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[41]  W. Robberecht,et al.  Mutational analysis of the Cu/Zn superoxide dismutase gene in 23 familial and 69 sporadic cases of amyotrophic lateral sclerosis in Belgium , 1999, European Journal of Human Genetics.

[42]  A. Malafosse,et al.  Identification of Six Novel SOD1 Gene Mutations in Familial Amyotrophic Lateral Sclerosis , 1998, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[43]  A. Al-Chalabi,et al.  Copper/zinc superoxide dismutase 1 and sporadic amyotrophic lateral sclerosis: Analysis of 155 cases and identification of novel insertion mutation , 1997, Annals of neurology.

[44]  P. Andersen,et al.  Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia. , 1997, Brain : a journal of neurology.

[45]  R W Orrell,et al.  Clinical and functional investigation of 10 missense mutations and a novel frameshift insertion mutation of the gene for copper-zinc superoxide dismutase in UK families with amyotrophic lateral sclerosis , 1997, Neurology.

[46]  H. Horvitz,et al.  Epidemiology of mutations in superoxide dismutase in amyotrophic lateal sclerosis , 1997, Annals of neurology.

[47]  David Haussler,et al.  Improved splice site detection in Genie , 1997, RECOMB '97.

[48]  M. Pericak-Vance,et al.  Prognosis in Familial Amyotrophic Lateral Sclerosis , 1997, Neurology.

[49]  H. Horvitz,et al.  Identification of three novel mutations in the gene for Cu Zn superoxide dismutase in patients with familial amyotrophic lateral sclerosis , 1995, Neuromuscular Disorders.

[50]  P. Andersen,et al.  Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase , 1995, Nature Genetics.

[51]  I. Kanazawa,et al.  A two basepair deletion in the SOD 1 gene causes familial amyotrophic lateral sclerosis. , 1994, Human molecular genetics.

[52]  M. Pericak-Vance,et al.  Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. , 1993, Science.

[53]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[54]  F. Corpet.  Multiple sequence alignment with hierarchical clustering. , 1988, Nucleic acids research.

[55]  Marvin B. Shapiro,et al.  RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. , 1987, Nucleic acids research.

[56]  V. Meininger,et al.  SOD 1 , ANG , VAPB , TARDBP , and FUS mutations in familial Amyotrophic Lateral Sclerosis : genotype-phenotype correlations , 2017 .

[57]  C. Carcassi,et al.  SOD1 mutations in amyotrophic lateral sclerosis. Results from a multicenter Italian study. , 2005, Journal of neurology.

[58]  G. Abecasis,et al.  Merlin—rapid analysis of dense genetic maps using sparse gene flow trees , 2002, Nature Genetics.

[59]  J. Tainer,et al.  Exon 5 encoded domain is not required for the toxic function of mutant SOD1 but essential for the dismutase activity: identification and characterization of two new SOD1 mutations associated with familial amyotrophic lateral sclerosis , 1997, Neurogenetics.