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Int. J. Mol. Sci. 2014, 15(6), 10350-10364;

Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome

Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain
Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, D-23538 Lübeck, Germany
Institut für Humangenetik, Universität zu Lübeck, D-23538 Lübeck, Germany
Department of Pediatrics, Hospital Pablo Tobon Uribe, 05001000 Medellín, Colombia
Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, E-28046 Madrid, Spain
Department of Pediatrics, Hematology, Oncology and Endocrinology and Department of General Nursery Medical University of Gdańsk, P80-211 Gdańsk, Poland
Department of Molecular Biology, Science School, National University of Rio Cuarto, 5800 Córdoba, Argentina
Genetics Clinic, Service of Pediatrics, University Clinic Hospital "Lozano Blesa", E-50009 Zaragoza, Spain
Authors to whom correspondence should be addressed.
Received: 9 April 2014 / Revised: 12 May 2014 / Accepted: 20 May 2014 / Published: 10 June 2014
(This article belongs to the Special Issue Pre-mRNA Splicing)
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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 ΔE10, ΔE12, ΔE33,34, and B’. 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. View Full-Text
Keywords: CdLS; NIPBL; splicing mutations; physiological splicing CdLS; NIPBL; splicing mutations; physiological splicing

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Teresa-Rodrigo, M.E.; Eckhold, J.; Puisac, B.; Dalski, A.; Gil-Rodríguez, M.C.; Braunholz, D.; Baquero, C.; Hernández-Marcos, M.; de Karam, J.C.; Ciero, M.; Santos-Simarro, F.; Lapunzina, P.; Wierzba, J.; Casale, C.H.; Ramos, F.J.; Gillessen-Kaesbach, G.; Kaiser, F.J.; Pié, J. Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome. Int. J. Mol. Sci. 2014, 15, 10350-10364.

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