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Int. J. Mol. Sci. 2014, 15(6), 10350-10364; doi:10.3390/ijms150610350
Article

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

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Received: 9 April 2014; in revised form: 12 May 2014 / Accepted: 20 May 2014 / Published: 10 June 2014
(This article belongs to the Special Issue Pre-mRNA Splicing)
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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.
Keywords: CdLS; NIPBL; splicing mutations; physiological splicing CdLS; NIPBL; splicing mutations; physiological splicing
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Teresa-Rodrigo, M.E.; Eckhold, J.; Puisac, B.; Dalski, A.; Gil-Rodríguez, M.C.; Braunholz, D.; Baquero, C.; Hernández-Marcos, M.; de Karam, J.C.; Ciero, M.; Santos-Simarro, F.; Lapunzina, P.; Wierzba, J.; Casale, C.H.; Ramos, F.J.; Gillessen-Kaesbach, G.; Kaiser, F.J.; Pié, J. Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome. Int. J. Mol. Sci. 2014, 15, 10350-10364.

AMA Style

Teresa-Rodrigo ME, Eckhold J, Puisac B, Dalski A, Gil-Rodríguez MC, Braunholz D, Baquero C, Hernández-Marcos M, de Karam JC, Ciero M, Santos-Simarro F, Lapunzina P, Wierzba J, Casale CH, Ramos FJ, Gillessen-Kaesbach G, Kaiser FJ, Pié J. Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome. International Journal of Molecular Sciences. 2014; 15(6):10350-10364.

Chicago/Turabian Style

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. 2014. "Functional Characterization of NIPBL Physiological Splice Variants and Eight Splicing Mutations in Patients with Cornelia de Lange Syndrome." Int. J. Mol. Sci. 15, no. 6: 10350-10364.



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