{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T08:41:41Z","timestamp":1792226501036,"version":"4.4.0"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"18","license":[{"start":{"date-parts":[[2020,9,15]],"date-time":"2020-09-15T00:00:00Z","timestamp":1600128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Italian Ministry of Health and Scientific Collaboration"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,11,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>SPONASTRIME dysplasia is an ultrarare spondyloepimetaphyseal dysplasia featuring short stature and short limbs, platyspondyly, depressed nasal bridge with midface hypoplasia and striated metaphyses. In 2019, an autosomal recessive inheritance was demonstrated by the identification of bi-allelic hypomorphic alleles in TONSL. The encoded protein has a critical role in maintaining genome integrity by promoting the homologous recombination required for repairing spontaneous replication-associated DNA lesions at collapsed replication forks. We report a 9-year-old girl with typical SPONASTRIME dysplasia and resulted in carrier of the novel missense p.(Gln430Arg) and p.(Leu1090Arg) variants in TONSL at whole-exome sequencing. In silico analysis predicted that these variants induced thermodynamic changes with a pathogenic impact on protein function. To support the pathogenicity of the identified variants, cytogenetic analysis and microscopy assays showed that patient-derived fibroblasts exhibited spontaneous chromosomal breaks and flow cytometry demonstrated defects in cell proliferation and enhanced apoptosis. These findings contribute to our understanding of the molecular pathogenesis of SPONASTRIME dysplasia and might open the way to novel therapeutic approaches.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa195","type":"journal-article","created":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T19:19:15Z","timestamp":1600456755000},"page":"3122-3131","source":"Crossref","is-referenced-by-count":8,"title":["Novel TONSL variants cause SPONASTRIME dysplasia and associate with spontaneous chromosome breaks, defective cell proliferation and apoptosis"],"prefix":"10.1093","volume":"29","author":[{"given":"Lucia","family":"Micale","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Cialfi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"Fusco","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigia","family":"Cinque","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Castellana","sequence":"additional","affiliation":[{"name":"Unit of Bioinformatics, Fondazione IRCCS, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Biagini","sequence":"additional","affiliation":[{"name":"Unit of Bioinformatics, Fondazione IRCCS, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Talora","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelantonio","family":"Notarangelo","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Bisceglia","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenica","family":"Taruscio","sequence":"additional","affiliation":[{"name":"Undiagnosed Rare Diseases Interdepartmental Unit, National Centre for Rare Diseases, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Salvatore","sequence":"additional","affiliation":[{"name":"Undiagnosed Rare Diseases Interdepartmental Unit, National Centre for Rare Diseases, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Castori","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,9,21]]},"reference":[{"key":"2020110605013153700_ref1","first-page":"267","article-title":"The SPONASTRIME dysplasia: familial short-limb dwarfism with saddle nose, spinal alterations and metaphyseal striation. 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