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DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in\n                    <jats:italic>DNAJB4<\/jats:italic>\n                    cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in\n                    <jats:italic>DNAJB4<\/jats:italic>\n                    in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547\u00a0C\u2009&gt;\u2009T, p.R183*; c.775\u00a0C\u2009&gt;\u2009T, p.R259*; an exon 2 deletion) and two missense variants (c.105G\u2009&gt;\u2009C, p.K35N; c.181\u00a0A\u2009&gt;\u2009G, p.R61G). All patients were homozygous. Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype\u2012phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J domain may predict a more severe phenotype.\n                  <\/jats:p>","DOI":"10.1186\/s40478-024-01878-w","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T05:17:06Z","timestamp":1730092626000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Genotype\u2012phenotype correlation in recessive DNAJB4 myopathy"],"prefix":"10.1186","volume":"12","author":[{"given":"Michio","family":"Inoue","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Divya","family":"Jayaraman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rocio","family":"Bengoechea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ankan","family":"Bhadra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casie A.","family":"Genetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdulrahman A.","family":"Aldeeri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bet\u00fcl","family":"Turan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael Adrian","family":"Pacheco-Orozco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Almundher","family":"Al-Maawali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia","family":"Al Hashmi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ay\u015fe G\u00fcl","family":"Zamani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emine","family":"G\u00f6kta\u015f","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sevgi","family":"Pekcan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanife Tu\u011f\u00e7e","family":"\u00c7a\u011flar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather","family":"True","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan H.","family":"Beggs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Conrad C.","family":"Weihl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,10,28]]},"reference":[{"key":"1878_CR1","doi-asserted-by":"publisher","unstructured":"Oliv\u00e9 M, Winter L, F\u00fcrst DO, Schr\u00f6der R, group E workshop study, Behin A et al (2021) 246th ENMC International Workshop: Protein aggregate myopathies 24\u201326 May 2019, Hoofddorp, The Netherlands. Neuromuscul Disord. ;31:158\u201366. https:\/\/doi.org\/10.1016\/j.nmd.2020.11.003","DOI":"10.1016\/j.nmd.2020.11.003"},{"key":"1878_CR2","doi-asserted-by":"publisher","unstructured":"Weihl CC, Udd B, Hanna M, group on behalf of the E workshop study, Ben-Zvi A, Blaettler T et al (2018) 234th ENMC International Workshop: Chaperone dysfunction in muscle disease Naarden, The Netherlands, 8\u201310 December 2017. Neuromuscul Disord. ;28:1022\u201330. https:\/\/doi.org\/10.1016\/j.nmd.2018.09.004","DOI":"10.1016\/j.nmd.2018.09.004"},{"key":"1878_CR3","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/bs.enz.2023.07.008","volume":"54","author":"SJ Ciesielski","year":"2023","unstructured":"Ciesielski SJ, Young C, Ciesielska EJ, Ciesielski GL (2023) The Hsp70 and JDP proteins: structure\u2013function perspective on molecular chaperone activity. 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This study was approved by the Institutional Review Board of Washington University School of Medicine (IRB #201103416) and Boston Children\u2019s Hospital (protocol 03-08-128R).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"171"}}