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

Authors
Teres Rodrigo, Maria; Eckhold, Juliane; Puisac, Beatriz; Dalski, Andreas; Gil Rodriguez, Maria C.; Braunholz, Diana; Baquero, Carolina; Hernández Marcos, Maria; de Karam, Juan C.; Ciero, Milagros; Santos Simarro, Fernando; Lapunzina, Pablo; Wierzba, Jolanta; Casale, Cesar Horacio; Ramos, Feliciano J.; Gillessen Kaesbach, Gabriele; Kaiser, Frank; Pie, Juan
Publication Year
2014
Language
English
Format
article
Status
Published version
Description
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
Fil: Teres Rodrigo, Maria. Universidad de Zaragoza; España
Fil: Eckhold, Juliane. Universität zu Lübeck; Alemania
Fil: Puisac, Beatriz. Universidad de Zaragoza; España
Fil: Dalski, Andreas. Universität zu Lübeck; Alemania
Fil: Gil Rodriguez, Maria C.. Universidad de Zaragoza; España
Fil: Braunholz, Diana. Universität zu Lübeck; Alemania
Fil: Baquero, Carolina. Universidad de Zaragoza; España. Hospital Pablo Tobon Uribe. Medellin; Colombia
Fil: Hernández Marcos, Maria. Universidad de Zaragoza; España
Fil: de Karam, Juan C.. Universidad de Zaragoza; España
Fil: Ciero, Milagros. Universidad de Zaragoza; España
Fil: Santos Simarro, Fernando. Hospital Universitario La Paz. Madrid; España
Fil: Lapunzina, Pablo. Hospital Universitario La Paz. Madrid; España
Fil: Wierzba, Jolanta. University of Gdańsk; Polonia
Fil: Casale, Cesar Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina
Fil: Ramos, Feliciano J.. Universidad de Zaragoza; España. University Clinic Hospital "Lozano Blesa"; España
Fil: Gillessen Kaesbach, Gabriele. Universität zu Lübeck; Alemania
Fil: Kaiser, Frank. Universität zu Lübeck; Alemania
Fil: Pie, Juan. Universidad de Zaragoza; España
Subject
CdLS
NIPBL
splicing mutations
physiological splicing
Otras Ciencias Biológicas
Ciencias Biológicas
CIENCIAS NATURALES Y EXACTAS
Access level
Open access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/34104