{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T14:17:26Z","timestamp":1754144246895,"version":"3.41.2"},"reference-count":29,"publisher":"The Endocrine Society","issue":"8","license":[{"start":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T00:00:00Z","timestamp":1733443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation for RCMG","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Pathogenic variants in the TBCE gene, encoding tubulin-specific chaperone E crucial for tubulin folding, are linked to three severe neurodevelopmental disorders: Hypoparathyroidism-retardation-dysmorphism syndrome, Kenny-Caffey syndrome type 1, and progressive encephalopathy with amyotrophy and optic atrophy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>We identified patients with a novel, milder TBCE-associated phenotype and aimed to characterize it at the clinical and molecular levels.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Materials and Methods<\/jats:title>\n                  <jats:p>We conducted splicing analysis using deep next-generation sequencing of RT-PCR products and detected TBCE through Western blotting. Translation efficiency was measured using a luciferase reporter assay. Overexpression experiments were performed in Hela cells with tubulin staining. Immunofluorescence analysis was used for Golgi complex assessment, while microtubule dynamics were studied post-nocodazole treatment. Electron microscopy facilitated ultrastructural studies.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We report 7 patients with a novel, milder TBCE phenotype, presenting with amyotrophy, testicular failure, and mild intellectual disability, with or without short stature. All patients were homozygous or compound-heterozygous for the NM_003193.5:c.100 + 1G &amp;gt; A variant, which causes a splicing alteration and early frameshift. However, we found that the mild phenotype arises due to translation from an alternative open reading frame, producing a partially functional protein. Dermal fibroblasts showed reduced Golgi compactness but normal microtubule dynamics. Electron microscopy revealed varying levels of acto-myosin degradation. The c.100 + 1G &amp;gt; A variant was found to be 10 times more frequent in Slavic samples than in gnomAD, suggesting underdiagnosis of this phenotype.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>This study uncovers complex molecular mechanisms contributing to the milder phenotype in patients with the c.100 + 1G &amp;gt; A variant, providing insights into a new TBCE-related disorder.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgae839","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T16:50:52Z","timestamp":1733849452000},"page":"e2485-e2497","source":"Crossref","is-referenced-by-count":0,"title":["Out-of-frame Translation Rescues a Loss-of-function Variant in a Novel <i>TBCE<\/i> Phenotype"],"prefix":"10.1210","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9160-0794","authenticated-orcid":false,"given":"Peter","family":"Sparber","sequence":"first","affiliation":[{"name":"Department of Functional Genomics, Research Centre for Medical Genetics , 115478 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evgeniia","family":"Ulas","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Institute of Protein Research of Russian Academy of Science , 142290 Moscow ,","place":["Russian Federation"]},{"name":"A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University , 119992 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5979-0727","authenticated-orcid":false,"given":"Alexandra","family":"Filatova","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Research Centre for Medical Genetics , 115478 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugene","family":"Tatarskiy","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Research Centre for Medical Genetics , 115478 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grigory","family":"Perelman","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Research Centre for Medical Genetics , 115478 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Makretskaya","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Research Centre for Medical Genetics , 115478 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Nagaeva","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Endocrinology, Endocrinology Research Centre , 117292 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Kareva","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Endocrinology, Endocrinology Research Centre , 117292 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Frolova","sequence":"additional","affiliation":[{"name":"Consulting and Diagnostic Department, National Medical Research Center for Children's Health Federal State Autonomous Institution of the Russian Federation Ministry of Health , 119991 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Kalinchenko","sequence":"additional","affiliation":[{"name":"Institute of Pediatric Endocrinology, Endocrinology Research Centre , 117292 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna V","family":"Tvorogova","sequence":"additional","affiliation":[{"name":"Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences , 119334 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergey","family":"Golyshev","sequence":"additional","affiliation":[{"name":"A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University , 119992 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anton","family":"Burakov","sequence":"additional","affiliation":[{"name":"A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University , 119992 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vyacheslav","family":"Tabakov","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Research Centre for Medical Genetics , 115478 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekaterina","family":"Lozier","sequence":"additional","affiliation":[{"name":"Independent Clinical Bioinformatics Laboratory , Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fedor","family":"Konovalov","sequence":"additional","affiliation":[{"name":"Independent Clinical Bioinformatics Laboratory , Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Voinova","sequence":"additional","affiliation":[{"name":"Clinical Genetics Department, Veltischev Research and Clinical Institute for Pediatrics Pirogov RNRMU , 125412 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anatoly","family":"Tiulpakov","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Research Centre for Medical Genetics , 115478 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7293-3438","authenticated-orcid":false,"given":"Mikhail","family":"Skoblov","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics, Research Centre for Medical Genetics , 115478 Moscow ,","place":["Russian Federation"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2024,12,6]]},"reference":[{"issue":"7","key":"2025071507131970800_dgae839-B1","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41580-018-0009-y","article-title":"Microtubule dynamics: an interplay of biochemistry and mechanics","volume":"19","author":"Brouhard","year":"2018","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2025071507131970800_dgae839-B2","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.sbi.2019.05.023","article-title":"Current approaches for the analysis of spindle organization","volume":"58","author":"Redemann","year":"2019","journal-title":"Curr Opin Struct Biol"},{"issue":"9","key":"2025071507131970800_dgae839-B3","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/j.semcdb.2011.09.017","article-title":"Regulation of cell migration by dynamic microtubules","volume":"22","author":"Kaverina","year":"2011","journal-title":"Semin Cell Dev Biol"},{"issue":"5991","key":"2025071507131970800_dgae839-B4","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/312237a0","article-title":"Dynamic instability of microtubule growth","volume":"312","author":"Mitchison","year":"1984","journal-title":"Nature"},{"issue":"5","key":"2025071507131970800_dgae839-B5","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.tibs.2009.12.007","article-title":"Quality control of cytoskeletal proteins and human disease","volume":"35","author":"Lundin","year":"2010","journal-title":"Trends Biochem Sci"},{"key":"2025071507131970800_dgae839-B6","doi-asserted-by":"crossref","first-page":"e08811","DOI":"10.7554\/eLife.08811","article-title":"Tubulin cofactors and Arl2 are cage-like chaperones that regulate the soluble alphabeta-tubulin pool for microtubule dynamics","volume":"4","author":"Nithianantham","year":"2015","journal-title":"Elife"},{"issue":"4","key":"2025071507131970800_dgae839-B7","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1083\/jcb.138.4.821","article-title":"Tubulin subunits exist in an activated conformational state generated and maintained by protein cofactors","volume":"138","author":"Tian","year":"1997","journal-title":"J Cell Biol"},{"issue":"34","key":"2025071507131970800_dgae839-B8","doi-asserted-by":"crossref","first-page":"24054","DOI":"10.1074\/jbc.274.34.24054","article-title":"Tubulin folding cofactors as GTPase-activating proteins. 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