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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Detalhes bibliográficos
Autores: 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
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2014
País:Argentina
Recursos:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositório:CONICET Digital (CONICET)
Idioma:inglês
OAI Identifier:oai:ri.conicet.gov.ar:11336/34104
Acesso em linha:http://hdl.handle.net/11336/34104
Access Level:Acceso aberto
Palavra-chave:CdLS
NIPBL
splicing mutations
physiological splicing
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
Descrição
Resumo: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

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