Functional characterization of NIPBL physiological splice variants and eight splicing mutations in patients with Cornelia de Lange syndrome.

Int J Mol Sci 2014 Jun 10;15(6):10350-64. Epub 2014 Jun 10.

Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, School of Medicine, University of Zaragoza, E-50009 Zaragoza, Spain.

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.

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms150610350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100155PMC
June 2014
168 Reads

Publication Analysis

Top Keywords

patients mutations
12
mutations nipbl
8
nipbl gene
8
lange syndrome
8
cornelia lange
8
mutations
6
nipbl
6
splicing
5
patients
5
Δe10 Δe12
4
rad21 functionally
4
functionally associated
4
identification splicing
4
nipbl hdac8
4
factors nipbl
4
associated factors
4
splicing isoforms
4
isoforms Δe10
4
smc1a smc3
4
splice-sites nipbl
4

Similar Publications