{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T19:37:22Z","timestamp":1790537842427,"version":"4.1.0"},"reference-count":85,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,21]],"date-time":"2021-08-21T00:00:00Z","timestamp":1629504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and cofunded with ERDF funds","award":["FIS PI18\/000687"],"award-info":[{"award-number":["FIS PI18\/000687"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>After 26 years of discovery of the determinant survival motor neuron 1 and the modifier survival motor neuron 2 genes (SMN1 and SMN2, respectively), three SMN-dependent specific therapies are already approved by FDA and EMA and, as a consequence, worldwide SMA patients are currently under clinical investigation and treatment. Bi-allelic pathogenic variants (mostly deletions) in SMN1 should be detected in SMA patients to confirm the disease. Determination of SMN2 copy number has been historically employed to correlate with the phenotype, predict disease evolution, stratify patients for clinical trials and to define those eligible for treatment. In view that discordant genotype-phenotype correlations are present in SMA, besides technical issues with detection of SMN2 copy number, we have hypothesized that copy number determination is only the tip of the iceberg and that more deepen studies of variants, sequencing and structures of the SMN2 genes are necessary for a better understanding of the disease as well as to investigate possible influences in treatment responses. Here, we highlight the importance of a comprehensive approach of SMN1 and SMN2 genetics with the perspective to apply for better prediction of SMA in positive neonatal screening cases and early diagnosis to start treatments.<\/jats:p>","DOI":"10.3390\/ijms22169029","type":"journal-article","created":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T21:47:52Z","timestamp":1629668872000},"page":"9029","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8949-9466","authenticated-orcid":false,"given":"Mar","family":"Costa-Roger","sequence":"first","affiliation":[{"name":"Medicine Genetics Group, Vall d\u2019Hebron Research Institute (VHIR), 08035 Barcelona, Spain"},{"name":"Department of Clinical and Molecular Genetics, Hospital Vall d\u2019Hebron, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6483-5742","authenticated-orcid":false,"given":"Laura","family":"Blasco-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Medicine Genetics Group, Vall d\u2019Hebron Research Institute (VHIR), 08035 Barcelona, Spain"},{"name":"Department of Clinical and Molecular Genetics, Hospital Vall d\u2019Hebron, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivon","family":"Cusc\u00f3","sequence":"additional","affiliation":[{"name":"Medicine Genetics Group, Vall d\u2019Hebron Research Institute (VHIR), 08035 Barcelona, Spain"},{"name":"Department of Clinical and Molecular Genetics, Hospital Vall d\u2019Hebron, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo F.","family":"Tizzano","sequence":"additional","affiliation":[{"name":"Medicine Genetics Group, Vall d\u2019Hebron Research Institute (VHIR), 08035 Barcelona, Spain"},{"name":"Department of Clinical and Molecular Genetics, Hospital Vall d\u2019Hebron, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.ncl.2015.07.004","article-title":"Spinal Muscular Atrophy","volume":"33","author":"Kolb","year":"2015","journal-title":"Neurol. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/ejhg.2011.134","article-title":"Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: Clinical laboratory analysis of >72,400 specimens","volume":"20","author":"Sugarman","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_3","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Mirzaa, G., and Amemiya, A. (2000). Spinal Muscular Atrophy. GeneReviews\u00ae, University of Washington. Available online: Website."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/gt.2017.52","article-title":"The clinical landscape for SMA in a new therapeutic era","volume":"24","author":"Talbot","year":"2017","journal-title":"Gene Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","article-title":"Identification and characterization of a spinal muscular atrophy-determining gene","volume":"80","author":"Lefebvre","year":"1995","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9","article-title":"An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA)","volume":"15","author":"Wirth","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1006\/geno.1996.0147","article-title":"Structure and organization of the human survival motor neurone (SMN) gene","volume":"32","author":"Lefebvre","year":"1996","journal-title":"Genomics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s004390100473","article-title":"SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens","volume":"108","author":"Rochette","year":"2001","journal-title":"Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s00439-019-01983-0","article-title":"Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype","volume":"138","author":"Ruhno","year":"2019","journal-title":"Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1002\/humu.24200","article-title":"Beyond copy number: A new, rapid, and versatile method for sequencing the entire SMN2 gene in SMA patients","volume":"42","author":"Paramonov","year":"2021","journal-title":"Hum. Mutat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6307","DOI":"10.1073\/pnas.96.11.6307","article-title":"A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy","volume":"96","author":"Lorson","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1093\/jnen\/64.3.215","article-title":"Implication of fetal SMN2 expression in type I SMA pathogenesis: Protection or pathological gain of function?","volume":"64","author":"Caselles","year":"2005","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.gde.2013.03.003","article-title":"How genetic modifiers influence the phenotype of spinal muscular atrophy and suggest future therapeutic approaches","volume":"23","author":"Wirth","year":"2013","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11696","DOI":"10.1038\/srep11696","article-title":"Decay in survival motor neuron and plastin 3 levels during differentiation of iPSC-derived human motor neurons","volume":"5","author":"Bernal","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.nmd.2018.01.003","article-title":"Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases","volume":"28","author":"Calucho","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.nmd.2006.08.011","article-title":"Multiplex ligation-dependent probe amplification improves diagnostics in spinal muscular atrophy","volume":"16","author":"Arkblad","year":"2006","journal-title":"Neuromuscul. Disord."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Vijzelaar, R., Snetselaar, R., Clausen, M., Mason, A.G., Rinsma, M., Zegers, M., Molleman, N., Boschloo, R., Yilmaz, R., and Kuilboer, R. (2019). The frequency of SMN gene variants lacking exon 7 and 8 is highly population dependent. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0220211"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1038\/s41436-020-0754-0","article-title":"Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data","volume":"22","author":"Chen","year":"2020","journal-title":"Genet. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1089\/gtmb.2010.0253","article-title":"Accuracy of marker analysis, quantitative real-time polymerase chain reaction, and multiple ligation-dependent probe amplification to determine SMN2 copy number in patients with spinal muscular atrophy","volume":"15","author":"Bernal","year":"2011","journal-title":"Genet. Test. Mol. Biomark."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/s004390000452","article-title":"Characterisation of SMN hybrid genes in Spanish SMA patients: De novo, homozygous and compound heterozygous cases","volume":"108","author":"Bussaglia","year":"2001","journal-title":"Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00439-008-0598-1","article-title":"Mutation update of spinal muscular atrophy in Spain: Molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene","volume":"125","author":"Bernal","year":"2009","journal-title":"Hum. Genet."},{"key":"ref_22","first-page":"1057","article-title":"Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: New insights into molecular mechanisms responsible for the disease","volume":"59","author":"Hahnen","year":"1996","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.braindev.2020.09.005","article-title":"Clinical phenotypes of spinal muscular atrophy patients with hybrid SMN gene","volume":"43","author":"Niba","year":"2021","journal-title":"Brain Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1136\/jmg.2009.066969","article-title":"Differences in SMN1 allele frequencies among ethnic groups within North America","volume":"46","author":"Hendrickson","year":"2009","journal-title":"J. Med. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/gim.2013.84","article-title":"An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy","volume":"16","author":"Luo","year":"2014","journal-title":"Genet. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1111\/cge.12222","article-title":"Improving detection and genetic counseling in carriers of spinal muscular atrophy with two copies of the SMN1 gene","volume":"85","author":"Bernal","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1038\/s41431-018-0193-4","article-title":"Utility of two SMN1 variants to improve spinal muscular atrophy carrier diagnosis and genetic counselling","volume":"26","author":"Bernal","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1002\/ana.25900","article-title":"Clinical Variability in Spinal Muscular Atrophy Type III","volume":"88","author":"Coratti","year":"2020","journal-title":"Ann. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejpn.2020.11.004","article-title":"Children and young adults with spinal muscular atrophy treated with nusinersen","volume":"30","author":"Osredkar","year":"2021","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.braindev.2020.07.012","article-title":"Natural history in spinal muscular atrophy Type I in Taiwanese population: A longitudinal study","volume":"43","author":"Ou","year":"2021","journal-title":"Brain Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1111\/ene.14587","article-title":"Clinical and radiological profile of patients with spinal muscular atrophy type 4","volume":"28","author":"Souza","year":"2021","journal-title":"Eur. J. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e18809","DOI":"10.1097\/MD.0000000000018809","article-title":"The analysis of the association between the copy numbers of survival motor neuron gene 2 and neuronal apoptosis inhibitory protein genes and the clinical phenotypes in 40 patients with spinal muscular atrophy: Observational study","volume":"99","author":"Zhang","year":"2020","journal-title":"Medicine (Baltim.)"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lusakowska, A., Jedrzejowska, M., Kaminska, A., Janiszewska, K., Grochowski, P., Zimowski, J., Sierdzinski, J., and Kostera-Pruszczyk, A. (2021). Observation of the natural course of type 3 spinal muscular atrophy: Data from the polish registry of spinal muscular atrophy. Orphanet J. Rare Dis., 16.","DOI":"10.1186\/s13023-021-01771-y"},{"key":"ref_34","first-page":"e1312","article-title":"Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: A cohort study","volume":"91","author":"Seferian","year":"2018","journal-title":"Neurology"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sun, Y., Kong, X., Zhao, Z., and Zhao, X. (2020). Mutation analysis of 419 family and prenatal diagnosis of 339 cases of spinal muscular atrophy in China. BMC Med. Genet., 21.","DOI":"10.1186\/s12881-020-01069-z"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.ajhg.2009.08.002","article-title":"A Positive Modifier of Spinal Muscular Atrophy in the SMN2 Gene","volume":"85","author":"Prior","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E1110","DOI":"10.1002\/humu.21173","article-title":"A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy","volume":"31","author":"Vezain","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1093\/hmg\/ddx166","article-title":"A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy","volume":"26","author":"Wu","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1136\/jmg.2010.079004","article-title":"The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor","volume":"47","author":"Bernal","year":"2010","journal-title":"J. Med. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1093\/hmg\/8.7.1177","article-title":"A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2","volume":"8","author":"Monani","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"676","DOI":"10.3389\/fneur.2021.663911","article-title":"SMA Identified: Clinical and Molecular Findings From a Sponsored Testing Program for Spinal Muscular Atrophy in More Than 2,000 Individuals","volume":"12","author":"Bowen","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e530","DOI":"10.1212\/NXG.0000000000000530","article-title":"Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy","volume":"6","author":"Bernal","year":"2020","journal-title":"Neurol. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.jmoldx.2016.05.004","article-title":"Mutation Spectrum of the Survival of Motor Neuron 1 and Functional Analysis of Variants in Chinese Spinal Muscular Atrophy","volume":"18","author":"Qu","year":"2016","journal-title":"J. Mol. Diagn."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.braindev.2021.03.006","article-title":"Phenotypes of SMA patients retaining SMN1 with intragenic mutation","volume":"43","author":"Wijaya","year":"2021","journal-title":"Brain Dev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1212\/01.WNL.0000132634.48815.13","article-title":"Detection of novel mutations in the SMN Tudor domain in type I SMA patients","volume":"63","author":"Baiget","year":"2004","journal-title":"Neurology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1007\/s00415-006-0410-x","article-title":"A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins","volume":"254","author":"Kotani","year":"2007","journal-title":"J. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/j.braindev.2013.11.009","article-title":"Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers in some spinal muscular atrophy (SMA) patients","volume":"36","author":"Yamamoto","year":"2014","journal-title":"Brain Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.braindev.2017.03.002","article-title":"SMA mutations in SMN Tudor and C-terminal domains destabilize the protein","volume":"39","author":"Takarada","year":"2017","journal-title":"Brain Dev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1093\/hmg\/5.11.1727","article-title":"An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: Further evidence for SMN as the primary SMA-determining gene","volume":"5","author":"Parsons","year":"1996","journal-title":"Hum. Mol. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1002\/ana.25549","article-title":"Severe brain involvement in 5q spinal muscular atrophy type 0","volume":"86","author":"Rocha","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/jhg.2015.16","article-title":"A new method for SMN1 and hybrid SMN gene analysis in spinal muscular atrophy using long-range PCR followed by sequencing","volume":"60","author":"Kubo","year":"2015","journal-title":"J. Hum. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e505","DOI":"10.1212\/NXG.0000000000000505","article-title":"Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy","volume":"6","author":"Matsui","year":"2020","journal-title":"Neurol. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1083\/jcb.200208079","article-title":"A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy","volume":"160","author":"Monani","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/braincomms\/fcaa075","article-title":"Intragenic and structural variation in the SMN locus and clinical variability in spinal muscular atrophy","volume":"2","author":"Wadman","year":"2020","journal-title":"Brain Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1212\/WNL.0000000000007836","article-title":"Discrepancy in redetermination of SMN2 copy numbers in children with SMA","volume":"93","author":"Schorling","year":"2019","journal-title":"Neurology"},{"key":"ref_56","first-page":"1","article-title":"Spinal muscular atrophy caused by a novel Alu-mediated deletion of exons 2a-5 in SMN1 undetectable with routine genetic testing","volume":"8","author":"Majer","year":"2020","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1093\/hmg\/ddn357","article-title":"Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition","volume":"18","author":"Hauke","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"E1509","DOI":"10.1073\/pnas.1616521114","article-title":"Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy","volume":"114","author":"Woo","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep11746","article-title":"Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches","volume":"5","author":"Nizzardo","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00415-005-0912-y","article-title":"SMN2 copy number predicts acute or chronic spinal muscular atrophy but does not account for intrafamilial variability in siblings","volume":"253","author":"Illa","year":"2006","journal-title":"J. Neurol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.ejpn.2016.07.017","article-title":"Genotype\u2013phenotype correlation of SMN locus genes in spinal muscular atrophy children from Argentina","volume":"20","author":"Medrano","year":"2016","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/jhg.2015.104","article-title":"Joint effect of the SMN2 and SERF1A genes on childhood-onset types of spinal muscular atrophy in Serbian patients","volume":"60","author":"Romac","year":"2015","journal-title":"J. Hum. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.tins.2020.11.009","article-title":"Spinal Muscular Atrophy: In the Challenge Lies a Solution","volume":"44","author":"Wirth","year":"2021","journal-title":"Trends Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1126\/science.1155085","article-title":"Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy","volume":"320","author":"Oprea","year":"2008","journal-title":"Science"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Wirth, B., Mendoza-Ferreira, N., and Torres-Benito, L. (2017). Chapter 12\u2014Spinal muscular atrophy disease modifiers. Spinal Muscular Atrophy: Disease Mechanisms and Therapy, Academic Press.","DOI":"10.1016\/B978-0-12-803685-3.00012-4"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/emboj.2010.19","article-title":"The splicing regulator Sam68 binds to a novel exonic splicing silencer and functions in SMN2 alternative splicing in spinal muscular atrophy","volume":"29","author":"Pedrotti","year":"2010","journal-title":"EMBO J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e87908","DOI":"10.1172\/jci.insight.87908","article-title":"Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy","volume":"1","author":"Powis","year":"2016","journal-title":"JCI Insight"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Zheleznyakova, G., Nilsson, E., Kiselev, A., Maretina, M., Tishchenko, L., Fredriksson, R., Baranov, V., and Schi\u00f6th, H. (2015). Methylation levels of SLC23A2 and NCOR2 genes correlate with spinal muscular atrophy severity. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121964"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4280","DOI":"10.1523\/JNEUROSCI.2728-12.2013","article-title":"Shift from extracellular signal-regulated kinase to AKT\/cAMP response element-binding protein pathway increases survival-motor-neuron expression in spinal-muscular-atrophy-like mice and patient cells","volume":"33","author":"Branchu","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.ajhg.2017.01.005","article-title":"Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis","volume":"100","author":"Riessland","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/mt.2014.209","article-title":"PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy","volume":"23","author":"Little","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00439-003-1025-2","article-title":"Evidence for a modifying pathway in SMA discordant families: Reduced SMN level decreases the amount of its interacting partners and Htra2-beta1","volume":"114","author":"Helmken","year":"2003","journal-title":"Hum. Genet."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1093\/jnen\/62.4.420","article-title":"Downregulation of Bcl-2 proteins in type I spinal muscular atrophy motor neurons during fetal development","volume":"62","author":"Ferrer","year":"2003","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.1172\/JCI60364","article-title":"Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway","volume":"121","author":"Farooq","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"7622","DOI":"10.1523\/JNEUROSCI.1245-05.2005","article-title":"Regular Exercise Prolongs Survival in a Type 2 Spinal Muscular Atrophy Model Mouse","volume":"25","author":"Grondard","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1056\/NEJMoa1702752","article-title":"Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy","volume":"377","author":"Finkel","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1056\/NEJMoa2009965","article-title":"Risdiplam in Type 1 Spinal Muscular Atrophy","volume":"384","author":"Baranello","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1056\/NEJMoa1706198","article-title":"Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy","volume":"377","author":"Mendell","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1212\/WNL.0000000000008207","article-title":"Combination therapy with nusinersen and AVXS-101 in SMA type 1","volume":"93","author":"Lee","year":"2019","journal-title":"Neurology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1177\/0883073820928784","article-title":"Clinical Course in a Patient With Spinal Muscular Atrophy Type 0 Treated With Nusinersen and Onasemnogene Abeparvovec","volume":"35","author":"Matesanz","year":"2020","journal-title":"J. Child Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/mus.27034","article-title":"Combination molecular therapies for type 1 spinal muscular atrophy","volume":"62","author":"Harada","year":"2020","journal-title":"Muscle Nerve"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1038\/s41593-021-00827-3","article-title":"Gain of toxic function by long-term AAV9-mediated SMN overexpression in the sensorimotor circuit","volume":"24","author":"Tattoli","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.ejpn.2020.07.001","article-title":"European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy","volume":"28","author":"Kirschner","year":"2020","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.nmd.2017.05.011","article-title":"Spinal muscular atrophy: A changing phenotype beyond the clinical trials","volume":"27","author":"Tizzano","year":"2017","journal-title":"Neuromuscul. Disord."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/jnc.14935","article-title":"Combined treatment with the histone deacetylase inhibitor LBH589 and a splice-switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in Spinal Muscular Atrophy cells","volume":"153","author":"Pagliarini","year":"2020","journal-title":"J. Neurochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/9029\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:48:49Z","timestamp":1760165329000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/9029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,21]]},"references-count":85,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22169029"],"URL":"https:\/\/doi.org\/10.3390\/ijms22169029","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,21]]}}}