title: Functional characterization of NIPBL physiological splice variants and eight splicing mutations in patients with Cornelia de Lange syndrome.
abstract: 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.
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain. eteresa@unizar.es.
authors.forename: María E
authors.initials: ME
authors.lastname: Teresa-Rodrigo
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, D-23538 Lübeck, Germany. Juliane.Eckhold@uksh.de.
authors.forename: Juliane
authors.initials: J
authors.lastname: Eckhold
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain. puisac@unizar.es.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Puisac
authors.affiliation: Institut für Humangenetik, Universität zu Lübeck, D-23538 Lübeck, Germany. andreas.dalski@uksh.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dalski
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain. mcgil@unizar.es.
authors.forename: María C
authors.initials: MC
authors.lastname: Gil-Rodríguez
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, D-23538 Lübeck, Germany. Diana.Braunholz@uksh.de.
authors.forename: Diana
authors.initials: D
authors.lastname: Braunholz
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain. carobaque@gmail.com.
authors.forename: Carolina
authors.initials: C
authors.lastname: Baquero
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain. mhmarcos@unizar.es.
authors.forename: María
authors.initials: M
authors.lastname: Hernández-Marcos
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain. ckaram78@yahoo.es.
authors.forename: Juan C
authors.initials: JC
authors.lastname: de Karam
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain. milagrosciero2005@yahoo.es.
authors.forename: Milagros
authors.initials: M
authors.lastname: Ciero
authors.affiliation: Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, E-28046 Madrid, Spain. fernando.santos@salud.madrid.org.
authors.forename: Fernando
authors.initials: F
authors.lastname: Santos-Simarro
authors.affiliation: Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, E-28046 Madrid, Spain. plapunzina.hulp@salud.madrid.org.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.affiliation: Department of Pediatrics, Hematology, Oncology and Endocrinology and Department of General Nursery Medical University of Gdańsk, P80-211 Gdańsk, Poland. kwierz@gumed.edu.pl.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Wierzba
authors.affiliation: Department of Molecular Biology, Science School, National University of Rio Cuarto, 5800 Córdoba, Argentina. ccasale@exa.unrc.edu.ar.
authors.forename: César H
authors.initials: CH
authors.lastname: Casale
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain. framos@unizar.es.
authors.forename: Feliciano J
authors.initials: FJ
authors.lastname: Ramos
authors.affiliation: Institut für Humangenetik, Universität zu Lübeck, D-23538 Lübeck, Germany. G.Gillessen@uksh.de.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, D-23538 Lübeck, Germany. frank.kaiser@uk-sh.de.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
authors.affiliation: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain. juanpie@unizar.es.
authors.forename: Juan
authors.initials: J
authors.lastname: Pié
mesh_terms: D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D003635:De Lange Syndrome / Q000235:genetics* / Q000473:pathology; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007223:Infant; D008297:Male; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; C487465:NIPBL protein, human; D020033:Protein Isoforms; D011506:Proteins