{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:13:57Z","timestamp":1787026437855,"version":"build-2736575974"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T00:00:00Z","timestamp":1722297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Spinal muscular atrophy (SMA) is caused by homozygous loss of the\n                      <jats:italic>SMN1<\/jats:italic>\n                      gene with\n                      <jats:italic>SMN2<\/jats:italic>\n                      gene copy number correlating with disease severity. Rarely SMA is caused by a deletion on one allele and a pathogenic variant on the other. The pathogenic missense variant c.5C&amp;gt;G (p.Ala2Gly) correlates with a mild disease phenotype that does not correlate with\n                      <jats:italic>SMN2<\/jats:italic>\n                      copy number. In a mouse model the c.5C&amp;gt;G transgene produces SMN that is thought to form partially functional SMN complexes, but levels in humans have not yet been investigated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We identified two patients with mild SMA caused by a heterozygous deletion of\n                      <jats:italic>SMN1<\/jats:italic>\n                      and the heterozygous variant, c.5C&amp;gt;G. Molecular findings were confirmed with deletion\/duplication analysis and Sanger sequencing. Skin fibroblasts were collected and cultured, and SMN expression was analyzed using immunofluorescence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Two patients with slowly progressing mild weakness were confirmed to have heterozygous pathogenic missense variant c.5C&amp;gt;G and a heterozygous deletion of\n                      <jats:italic>SMN1<\/jats:italic>\n                      . Their clinical presentation revealed much milder disease progression than patients with matched\n                      <jats:italic>SMN2<\/jats:italic>\n                      copy number. Analysis of the patients\u2019 fibroblasts revealed much higher numbers of SMN nuclear complexes than a patient with a homozygous\n                      <jats:italic>SMN1<\/jats:italic>\n                      deletion and matched\n                      <jats:italic>SMN2<\/jats:italic>\n                      copy number.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These case reports reinforce that the rare c.5C&amp;gt;G variant causes mild disease. Furthermore, the analysis of SMA nuclear gems in patient samples supports the theory that the p.Ala2Gly SMN can form partially functional SMN complexes that may carry out essential cellular functions and result in mild disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2024.1406819","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T00:22:11Z","timestamp":1722298931000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["SMN1 c.5C&gt;G (p.Ala2Gly) missense variant, a challenging molecular SMA diagnosis associated with mild disease, preserves SMN nuclear gems in patient-specific fibroblasts"],"prefix":"10.3389","volume":"15","author":[{"given":"Sara L.","family":"Cook","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Stout","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Kirkeby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noemi","family":"Vidal-Folch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devin","family":"Oglesbee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Hasadsri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duygu","family":"Selcen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Milone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan P.","family":"Staff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3390\/mps7010009","article-title":"Assessment of nuclear gem quantity for evaluating the efficacy of antisense oligonucleotides in spinal muscular atrophy cells","volume":"7","author":"Al-Hilal","year":"2024","journal-title":"Methods Protocols"},{"key":"B2","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/j.nmd.2023.03.001","article-title":"Novel Alu-mediated deletions of the SMN1 gene were identified by ultra-long read sequencing technology in patients with spinal muscular atrophy","volume":"33","author":"Bai","year":"2023","journal-title":"Neuromuscul. 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