Τίτλος:
New type of disease causing mutations: the example of the composite
exonic regulatory elements of splicing in CFTR exon 12
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
The increase in genome scanning data, derived from clinical genetics
practice, is producing a wealth of information on human sequence
variability. The critical issue is to identify if a given nucleotide
change results in a benign polymorphism or a disease-causing mutation.
We have focused on one specific gene expression step, pre-mRNA
processing, where we can functionally define the effect of nucleotide
changes and in turn the patient’s mutation can shed light on the basic
pre mRNA splicing mechanisms. Our results show that several nucleotide
changes in CFTR exon 12 induce a variable extent of exon skipping that
leads to reduced levels of normal transcripts. This is the case in both
natural mutations D565G and G576A (the latter having previously
considered a neutral polymorphism) and several site-directed silent
substitutions. We demonstrate here that this phenomenon is due to the
interference with a new regulatory element that we have named composite
exonic regulatory element of splicing (CERES). The effect of single
nucleotide substitutions at CERES cannot be predicted by neither SR
matrices nor enhancer identification. The recognition and
characterization of splicing abnormalities, caused by exon sequence
variations at CERES elements, may represent a frequent disease-causing
mechanism that also relates to the phenotypic variability. Our results
indicate that even the most benign looking polymorphism in an exon
cannot be ignored as it may affect the splicing process. Hence,
appropriate functional splicing assays should be included in genotype
screenings to distinguish between polymorphisms; and pathogenic
mutations.
Συγγραφείς:
Pagani, F
Stuani, C
Tzetis, M
Kanavakis, E
Efthymiadou,
A
Doudounakis, S
Casals, T
Baralle, FE
Περιοδικό:
Human Molecular Genetics
Εκδότης:
Oxford University Press
