{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:26:54Z","timestamp":1791473214775,"version":"4.3.4"},"reference-count":28,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T00:00:00Z","timestamp":1766880000000},"content-version":"vor","delay-in-days":361,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n                    Distal arthrogryposis (DA) is a group of nonprogressive congenital muscular disorders affecting distal limb joints, without concurrent neuromuscular disease. Ten different types of DAs are known, with many different genes involved. Dominant variants in\n                    <jats:italic>TNNT3<\/jats:italic>\n                    (MIM \u2217600692) cause DA type 2B2 (MIM #618435), a severe condition featuring dysmorphism, distal contractures, and deformities of hands and feet.\n                    <jats:italic>TNNT3<\/jats:italic>\n                    encodes the fast skeletal troponin T, an essential component of the troponin complex that is necessary for calcium\u2010coupled contraction initiation in the striated muscle. Recently, homozygous splicing variants in\n                    <jats:italic>TNNT3<\/jats:italic>\n                    have been reported in two subjects with a distinctive congenital myopathy, only partially overlapping DA2B2. However, no functional evidence was provided. In this study, we investigated two patients presenting with myopathic conditions at different ends of the\n                    <jats:italic>TNNT3<\/jats:italic>\n                    spectrum. One subject showed DA, whereas the second displayed a severe congenital myopathy featuring hypotonia, DA, and dysmorphism. Through exome sequencing, we identified the de novo missense change p.(Arg63His) in Subject #1 and biallelic\n                    <jats:italic>TNNT3<\/jats:italic>\n                    variants in Subject #2, featuring a splicing and a stop gain variant. The p.(Arg63His) was predicted to affect the stability of troponin T3 in silico, and we confirmed this by western blot. Then, employing different biochemical approaches, we showed that the truncated variants identified in #2 (p.[Tyr13\u2217] and c.480+5G&gt;A) lead to loss of the full\u2010length protein. Our findings refine and expand the\n                    <jats:italic>TNNT3<\/jats:italic>\n                    genotype\u2013phenotype spectrum, suggesting that recessive\n                    <jats:italic>TNNT3<\/jats:italic>\n                    \u2010related congenital myopathy should be considered a discrete entity caused by biallelic loss\u2010of\u2010function variants.\n                  <\/jats:p>","DOI":"10.1155\/humu\/1785045","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T04:37:03Z","timestamp":1766983023000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Emerging\n                    <i>TNNT3<\/i>\n                    Spectrum: From Distal Arthrogryposis to Congenital Myopathy"],"prefix":"10.1155","volume":"2025","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5321-7447","authenticated-orcid":false,"given":"Nami","family":"Altin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0323-9290","authenticated-orcid":false,"given":"Kamel","family":"Mamchaoui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0989-2003","authenticated-orcid":false,"given":"Jessica","family":"Ohana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0337-5425","authenticated-orcid":false,"given":"Anne","family":"Bigot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9510-9388","authenticated-orcid":false,"given":"Beatrice","family":"Corradi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5705-6967","authenticated-orcid":false,"given":"Luca","family":"Maragliano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7807-1322","authenticated-orcid":false,"given":"Francesca","family":"Madia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3698-9319","authenticated-orcid":false,"given":"Marzia","family":"Ognibene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5762-0601","authenticated-orcid":false,"given":"Mohammad Sadegh Shams","family":"Nosrati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5102-6062","authenticated-orcid":false,"given":"Dario","family":"Paladini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4788-9719","authenticated-orcid":false,"given":"Michele","family":"Iacomino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asma","family":"Rashid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Bodamer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8503-6111","authenticated-orcid":false,"given":"Susana","family":"Quijano-Roy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6774-4464","authenticated-orcid":false,"given":"Jaya","family":"Punetha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3097-0388","authenticated-orcid":false,"given":"Valeria","family":"Capra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9744-5222","authenticated-orcid":false,"given":"Federico","family":"Zara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4838-3712","authenticated-orcid":false,"given":"Capucine","family":"Trollet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2194-7239","authenticated-orcid":false,"given":"Marcello","family":"Scala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,28]]},"reference":[{"key":"e_1_2_11_1_2","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.I.00281"},{"key":"e_1_2_11_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35809"},{"key":"e_1_2_11_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00689"},{"key":"e_1_2_11_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38593"},{"key":"e_1_2_11_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/376418"},{"key":"e_1_2_11_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2011.03.002"},{"key":"e_1_2_11_7_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-6899com"},{"key":"e_1_2_11_8_2","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000649"},{"key":"e_1_2_11_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adg2841"},{"key":"e_1_2_11_10_2","doi-asserted-by":"publisher","DOI":"10.1159\/000365057"},{"key":"e_1_2_11_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11999-008-0694-5"},{"key":"e_1_2_11_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23385"},{"key":"e_1_2_11_13_2","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000589"},{"key":"e_1_2_11_14_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-021-00973-0"},{"key":"e_1_2_11_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2016.01.006"},{"key":"e_1_2_11_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-85766-4_12"},{"key":"e_1_2_11_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.22407"},{"key":"e_1_2_11_18_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22179187"},{"key":"e_1_2_11_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-023-01516-4"},{"key":"e_1_2_11_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcla.24089"},{"key":"e_1_2_11_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac106"},{"key":"e_1_2_11_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24015"},{"key":"e_1_2_11_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-022-01488-1"},{"key":"e_1_2_11_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26585"},{"key":"e_1_2_11_25_2","doi-asserted-by":"publisher","DOI":"10.1088\/1361-6463\/abedfb"},{"key":"e_1_2_11_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_11_27_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.955041"},{"key":"e_1_2_11_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2010.06.001"}],"container-title":["Human 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