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

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...

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Autores principales: Teresa-Rodrigo, María E., Eckhold, Juliane, Puisac, Beatriz, Dalski, Andreas, Gil-Rodríguez, María C., Braunholz, Diana, Baquero, Carolina, Hernández-Marcos, María, de Karam, Juan C., Ciero, Milagros, Santos-Simarro, Fernando, Lapunzina, Pablo, Wierzba, Jolanta, Casale, César H., Ramos, Feliciano J., Gillessen-Kaesbach, Gabriele, Kaiser, Frank J., Pié, Juan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100155/
https://www.ncbi.nlm.nih.gov/pubmed/24918291
http://dx.doi.org/10.3390/ijms150610350
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author Teresa-Rodrigo, María E.
Eckhold, Juliane
Puisac, Beatriz
Dalski, Andreas
Gil-Rodríguez, María C.
Braunholz, Diana
Baquero, Carolina
Hernández-Marcos, María
de Karam, Juan C.
Ciero, Milagros
Santos-Simarro, Fernando
Lapunzina, Pablo
Wierzba, Jolanta
Casale, César H.
Ramos, Feliciano J.
Gillessen-Kaesbach, Gabriele
Kaiser, Frank J.
Pié, Juan
author_facet Teresa-Rodrigo, María E.
Eckhold, Juliane
Puisac, Beatriz
Dalski, Andreas
Gil-Rodríguez, María C.
Braunholz, Diana
Baquero, Carolina
Hernández-Marcos, María
de Karam, Juan C.
Ciero, Milagros
Santos-Simarro, Fernando
Lapunzina, Pablo
Wierzba, Jolanta
Casale, César H.
Ramos, Feliciano J.
Gillessen-Kaesbach, Gabriele
Kaiser, Frank J.
Pié, Juan
author_sort Teresa-Rodrigo, María E.
collection PubMed
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.
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spelling pubmed-41001552014-07-16 Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome Teresa-Rodrigo, María E. Eckhold, Juliane Puisac, Beatriz Dalski, Andreas Gil-Rodríguez, María C. Braunholz, Diana Baquero, Carolina Hernández-Marcos, María de Karam, Juan C. Ciero, Milagros Santos-Simarro, Fernando Lapunzina, Pablo Wierzba, Jolanta Casale, César H. Ramos, Feliciano J. Gillessen-Kaesbach, Gabriele Kaiser, Frank J. Pié, Juan Int J Mol Sci Article 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. MDPI 2014-06-10 /pmc/articles/PMC4100155/ /pubmed/24918291 http://dx.doi.org/10.3390/ijms150610350 Text en © 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Teresa-Rodrigo, María E.
Eckhold, Juliane
Puisac, Beatriz
Dalski, Andreas
Gil-Rodríguez, María C.
Braunholz, Diana
Baquero, Carolina
Hernández-Marcos, María
de Karam, Juan C.
Ciero, Milagros
Santos-Simarro, Fernando
Lapunzina, Pablo
Wierzba, Jolanta
Casale, César H.
Ramos, Feliciano J.
Gillessen-Kaesbach, Gabriele
Kaiser, Frank J.
Pié, Juan
Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome
title Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome
title_full Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome
title_fullStr Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome
title_full_unstemmed Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome
title_short Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome
title_sort functional characterization of nipbl physiological splice variants and eight splicing mutations in patients with cornelia de lange syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100155/
https://www.ncbi.nlm.nih.gov/pubmed/24918291
http://dx.doi.org/10.3390/ijms150610350
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