{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:48:28Z","timestamp":1784555308876,"version":"3.55.0"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2020,3,11]],"date-time":"2020-03-11T00:00:00Z","timestamp":1583884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"National Institute of Health"},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal Diseases","doi-asserted-by":"crossref","award":["R01AR068429"],"award-info":[{"award-number":["R01AR068429"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD075802"],"award-info":[{"award-number":["R01HD075802"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["MDA602235"],"award-info":[{"award-number":["MDA602235"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007857","name":"Intellectual and Developmental Disabilities Research Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007857","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"NICHD","doi-asserted-by":"publisher","award":["U54HD090255"],"award-info":[{"award-number":["U54HD090255"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cofilin-2 is an actin-binding protein that is predominantly expressed in skeletal and cardiac muscles and belongs to the AC group of proteins, which includes cofilin-1 and destrin. In humans, cofilin-2 (CFL2) mutations have been associated with congenital myopathies that include nemaline and myofibrillar myopathy. To understand the pathogenicity of the human CFL2 mutation, p.A35T, that first linked cofilin-2 with the human disease, we created a knock-in mouse model. The Cfl2A35T\/A35T (KI) mice were indistinguishable from their wild-type littermates at birth, but they rapidly worsened and died by postnatal day 9. The phenotypic, histopathologic and molecular findings mimicked the constitutive Cfl2-knockout (KO) mice described previously, including sarcomeric disruption and actin accumulations in skeletal muscles and negligible amounts of cofilin-2 protein. In addition, KI mice demonstrated a marked reduction in Cfl2 mRNA levels in various tissues including skeletal muscles. Further investigation revealed evidence of alternative splicing with the presence of two alternate transcripts of smaller size. These alternate transcripts were expressed at very low levels in the wild-type mice and were significantly upregulated in the mutant mice, indicating that pre-translational splicing defects may be a critical component of the disease mechanism associated with the mutation. Evidence of reduced expression of the full-length CFL2 transcript was also observed in the muscle biopsy sample of the patient with p.A35T mutation.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa035","type":"journal-article","created":{"date-parts":[[2020,3,8]],"date-time":"2020-03-08T12:25:02Z","timestamp":1583670302000},"page":"1996-2003","source":"Crossref","is-referenced-by-count":8,"title":["Knockin mouse model of the human CFL2 p.A35T mutation results in a unique splicing defect and severe myopathy phenotype"],"prefix":"10.1093","volume":"29","author":[{"given":"Samantha M","family":"Rosen","sequence":"first","affiliation":[{"name":"Division of Newborn Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mugdha","family":"Joshi","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia","family":"Hitt","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan H","family":"Beggs","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj B","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,3,11]]},"reference":[{"key":"2020073002370737200_ref1","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1136\/jmg.34.9.705","article-title":"Nemaline myopathy: current concepts. The ENMC International Consortium and Nemaline Myopathy","volume":"34","author":"North","year":"1997","journal-title":"J. Med. Genet."},{"key":"2020073002370737200_ref2","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1212\/01.WNL.0000046585.81304.BC","article-title":"Clinical course correlates poorly with muscle pathology in nemaline myopathy","volume":"60","author":"Ryan","year":"2003","journal-title":"Neurology"},{"key":"2020073002370737200_ref3","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1002\/ana.1080","article-title":"Nemaline myopathy: a clinical study of 143 cases","volume":"50","author":"Ryan","year":"2001","journal-title":"Ann. Neurol."},{"key":"2020073002370737200_ref4","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/S1471-4914(01)02089-5","article-title":"Clinical and genetic heterogeneity in nemaline myopathy\u2014a disease of skeletal muscle thin filaments","volume":"7","author":"Sanoudou","year":"2001","journal-title":"Trends Mol. Med."},{"key":"2020073002370737200_ref5","doi-asserted-by":"crossref","first-page":"99","DOI":"10.3233\/JND-160200","article-title":"Sarcomere dysfunction in Nemaline myopathy","volume":"4","author":"Winter","year":"2017","journal-title":"J. Neuromuscul. Dis."},{"key":"2020073002370737200_ref6","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1086\/510402","article-title":"Nemaline myopathy with minicores caused by mutation of the CFL2 gene encoding the skeletal muscle actin-binding protein, cofilin-2","volume":"80","author":"Agrawal","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"2020073002370737200_ref7","doi-asserted-by":"crossref","first-page":"S186","DOI":"10.1016\/j.nmd.2017.06.336","article-title":"Congenital myopathy with protein aggregates and nemaline bodies related to CFL2 mutations","volume":"27","author":"Fattori","year":"2017","journal-title":"Neuromuscul. Disord."},{"key":"2020073002370737200_ref8","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1111\/cge.13240","article-title":"Expanding the histopathological spectrum of CFL2-related myopathies","volume":"93","author":"Fattori","year":"2018","journal-title":"Clin. Genet."},{"key":"2020073002370737200_ref9","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.nmd.2012.03.008","article-title":"Congenital myopathy caused by a novel missense mutation in the CFL2 gene","volume":"22","author":"Ockeloen","year":"2012","journal-title":"Neuromuscul. Disord."},{"key":"2020073002370737200_ref10","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1136\/jnnp-2014-307608","article-title":"Novel cofilin-2 (CFL2) four base pair deletion causing nemaline myopathy","volume":"85","author":"Ong","year":"2014","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"2020073002370737200_ref11","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1093\/hmg\/dds053","article-title":"Normal myofibrillar development followed by progressive sarcomeric disruption with actin accumulations in a mouse Cfl2 knockout demonstrates requirement of cofilin-2 for muscle maintenance","volume":"21","author":"Agrawal","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"2020073002370737200_ref12","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.ejcb.2014.01.007","article-title":"Severe protein aggregate myopathy in a knockout mouse model points to an essential role of cofilin2 in sarcomeric actin exchange and muscle maintenance","volume":"93","author":"Gurniak","year":"2014","journal-title":"Eur. J. Cell Biol."},{"key":"2020073002370737200_ref13","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1146\/annurev.cellbio.15.1.185","article-title":"Proteins of the ADF\/cofilin family: essential regulators of actin dynamics","volume":"15","author":"Bamburg","year":"1999","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"2020073002370737200_ref14","doi-asserted-by":"crossref","first-page":"7127","DOI":"10.1021\/bi049797n","article-title":"In vitro activity differences between proteins of the ADF\/cofilin family define two distinct subgroups","volume":"43","author":"Chen","year":"2004","journal-title":"Biochemistry"},{"key":"2020073002370737200_ref15","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/83762","article-title":"A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes","volume":"27","author":"Liu","year":"2001","journal-title":"Nat. Genet."},{"key":"2020073002370737200_ref16","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s10549-009-0392-3","article-title":"The c.5242C&gt;A BRCA1 missense variant induces exon skipping by increasing splicing repressors binding","volume":"120","author":"Millevoi","year":"2010","journal-title":"Breast Cancer Res. Treat."},{"key":"2020073002370737200_ref17","doi-asserted-by":"crossref","first-page":"4906","DOI":"10.3892\/mmr.2016.5819","article-title":"Exon 10 skipping in ACAT1 caused by a novel c.949G&gt;A mutation located at an exonic splice enhancer site","volume":"14","author":"Otsuka","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"2020073002370737200_ref18","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1089\/gte.2006.10.116","article-title":"A missense mutation in exon 13 in BRCA2, c.7235G&gt;A, results in skipping of exon 13","volume":"10","author":"Thomassen","year":"2006","journal-title":"Genet. Test."},{"key":"2020073002370737200_ref19","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1093\/hmg\/ddg222","article-title":"Aberrant splicing induced by missense mutations in BRCA1: clues from a humanized mouse model","volume":"12","author":"Yang","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"2020073002370737200_ref20","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1002\/humu.20103","article-title":"Disruption of exonic splicing enhancer elements is the principal cause of exon skipping associated with seven nonsense or missense alleles of NF1","volume":"24","author":"Zatkova","year":"2004","journal-title":"Hum. Mutat."},{"key":"2020073002370737200_ref21","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/S0968-0004(00)01549-8","article-title":"Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases","volume":"25","author":"Blencowe","year":"2000","journal-title":"Trends Biochem. Sci."},{"key":"2020073002370737200_ref22","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/ng854","article-title":"Disruption of an SF2\/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1","volume":"30","author":"Cartegni","year":"2002","journal-title":"Nat. Genet."},{"key":"2020073002370737200_ref23","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1086\/342192","article-title":"BRCA2 T2722R is a deleterious allele that causes exon skipping","volume":"71","author":"Fackenthal","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"2020073002370737200_ref24","doi-asserted-by":"crossref","first-page":"3523","DOI":"10.1158\/0008-5472.CAN-07-1587","article-title":"Functional assays for classification of BRCA2 variants of uncertain significance","volume":"68","author":"Farrugia","year":"2008","journal-title":"Cancer Res."},{"key":"2020073002370737200_ref25","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nrg1327","article-title":"Genomic variants in exons and introns: identifying the splicing spoilers","volume":"5","author":"Pagani","year":"2004","journal-title":"Nat. Rev. Genet."},{"key":"2020073002370737200_ref26","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1093\/nar\/gkp215","article-title":"Human splicing finder: an online bioinformatics tool to predict splicing signals","volume":"37","author":"Desmet","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2020073002370737200_ref27","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1212\/WNL.59.4.613","article-title":"Mutations of the slow muscle alpha-tropomyosin gene, TPM3, are a rare cause of nemaline myopathy","volume":"59","author":"Wattanasirichaigoon","year":"2002","journal-title":"Neurology"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddaa035\/33438982\/ddaa035.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/29\/12\/1996\/33542368\/ddaa035.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/29\/12\/1996\/33542368\/ddaa035.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,30]],"date-time":"2020-07-30T06:37:53Z","timestamp":1596091073000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/29\/12\/1996\/5803133"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,11]]},"references-count":27,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,3,11]]},"published-print":{"date-parts":[[2020,7,29]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddaa035","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,6,15]]},"published":{"date-parts":[[2020,3,11]]}}}