{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T14:11:12Z","timestamp":1761919872485,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2014,6,10]],"date-time":"2014-06-10T00:00:00Z","timestamp":1402358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by distinctive craniofacial features, growth retardation, cognitive impairment, limb defects, hirsutism, and multisystem involvement. Mutations in five genes encoding structural components (SMC1A, SMC3, RAD21) or functionally associated factors (NIPBL, HDAC8) of the cohesin complex have been found in patients with CdLS. In about 60%  of the patients, mutations in NIPBL could be identified. Interestingly, 17% of them are predicted to change normal splicing, however, detailed molecular investigations are often missing. Here, we report the first systematic study of the physiological splicing of the NIPBL gene, that would reveal the identification of four new splicing isoforms \u0394E10, \u0394E12, \u0394E33,34, and B\u2019. Furthermore, we have investigated nine mutations affecting  splice-sites in the NIPBL gene identified in twelve CdLS patients. All mutations have been examined on the DNA and RNA level, as well as by in silico analyses. Although patients with mutations affecting NIPBL splicing show a broad clinical variability, the more severe phenotypes seem to be associated with aberrant transcripts resulting in a shift of the reading frame.<\/jats:p>","DOI":"10.3390\/ijms150610350","type":"journal-article","created":{"date-parts":[[2014,6,10]],"date-time":"2014-06-10T11:50:51Z","timestamp":1402401051000},"page":"10350-10364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with  Cornelia de Lange Syndrome"],"prefix":"10.3390","volume":"15","author":[{"given":"Mar\u00eda","family":"Teresa-Rodrigo","sequence":"first","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology  and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliane","family":"Eckhold","sequence":"additional","affiliation":[{"name":"Sektion f\u00fcr Funktionelle Genetik am Institut f\u00fcr Humangenetik, Universit\u00e4t zu L\u00fcbeck,  D-23538 L\u00fcbeck, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0170-7326","authenticated-orcid":false,"given":"Beatriz","family":"Puisac","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology  and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Dalski","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Humangenetik, Universit\u00e4t zu L\u00fcbeck, D-23538 L\u00fcbeck, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"Gil-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology  and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Braunholz","sequence":"additional","affiliation":[{"name":"Sektion f\u00fcr Funktionelle Genetik am Institut f\u00fcr Humangenetik, Universit\u00e4t zu L\u00fcbeck,  D-23538 L\u00fcbeck, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Baquero","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology  and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain"},{"name":"Department of Pediatrics, Hospital Pablo Tobon Uribe, 05001000 Medell\u00edn, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"Hern\u00e1ndez-Marcos","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology  and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"De Karam","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology  and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milagros","family":"Ciero","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology  and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1201-9118","authenticated-orcid":false,"given":"Fernando","family":"Santos-Simarro","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, E-28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Lapunzina","sequence":"additional","affiliation":[{"name":"Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, E-28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jolanta","family":"Wierzba","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hematology, Oncology and Endocrinology and Department of General Nursery Medical University of Gda\u0144sk, P80-211 Gda\u0144sk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9sar","family":"Casale","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Science School, National University of Rio Cuarto,  5800 C\u00f3rdoba, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5732-2209","authenticated-orcid":false,"given":"Feliciano","family":"Ramos","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology  and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain"},{"name":"Genetics Clinic, Service of Pediatrics, University Clinic Hospital \"Lozano Blesa\",  E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Gillessen-Kaesbach","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Humangenetik, Universit\u00e4t zu L\u00fcbeck, D-23538 L\u00fcbeck, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Sektion f\u00fcr Funktionelle Genetik am Institut f\u00fcr Humangenetik, Universit\u00e4t zu L\u00fcbeck,  D-23538 L\u00fcbeck, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3203-6254","authenticated-orcid":false,"given":"Juan","family":"Pi\u00e9","sequence":"additional","affiliation":[{"name":"Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology  and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2014,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1002\/ajmg.a.31757","article-title":"Cornelia de Lange syndrome: Clinical review, diagnostic and 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