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

International Journal of Molecular Sciences

Mar໚ E. Teresa-Rodrigo¹  Juliane Eckhold²  Beatriz Puisac¹  Andreas Dalski⁵  Mar໚ C. Gil-Rodríguez¹  Diana Braunholz²  Carolina Baquero¹  Mar໚ Hernández-Marcos¹  Juan C. de Karam¹  Milagros Ciero¹  Fernando Santos-Simarro⁴  Pablo Lapunzina⁴  Jolanta Wierzba⁶  César H. Casale³  Feliciano J. Ramos¹  Gabriele Gillessen-Kaesbach⁵  Frank J. Kaiser² 

[1] Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain; E-Mails:;Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, D-23538 Lübeck, Germany; E-Mails:;Department of Molecular Biology, Science School, National University of Rio Cuarto, 5800 Córdoba, Argentina; E-Mail:;Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, E-28046 Madrid, Spain; E-Mails:;Institut für Humangenetik, Universität zu Lübeck, D-23538 Lübeck, Germany; E-Mails:;Department of Pediatrics, Hematology, Oncology and Endocrinology and Department of General Nursery Medical University of Gdańsk, P80-211 Gdańsk, Poland; E-Mail:

关键词: CdLS;    NIPBL;    splicing mutations;    physiological splicing;   

DOI  :  10.3390/ijms150610350

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.