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Abstract
X-linked Alport syndrome (XLAS) is a congenital renal disease caused by mutations in COL4A5. In XLAS cases suspected of being caused by aberrant splicing, transcript analysis needs to be conducted to determine splicing patterns and assess the pathogenicity. However, such analysis is not always available. We conducted a functional splicing assay using a hybrid minigene for seven COL4A5 intronic mutations: one was identified by us and six were found in the Human Gene Mutation Database. The minigene assay revealed exon skipping in four variants, exon skipping and a 10-bp insertion in one variant, and no change in one variant, which appeared not to be pathogenic. For one variant, our assay did not work. The results of all three cases for which transcript data were available were consistent with our assay results. Our findings may help to increase the accuracy of genetic test results and clarify the mechanisms causing aberrant splicing.
Highlights
X-linked Alport syndrome (XLAS) is a congenital renal disease caused by mutations in COL4A5
No branch point alteration was observed. This is the first report comprehensively exploring COL4A5 splicing patterns in variants assumed to be pathogenic in intronic regions 10 to 40 bp upstream of exons
XLAS is a monogenic disease caused by COL4A5, pathogenic COL4A5 mutations are not detected in all clinically diagnosed XLAS patients
Summary
X-linked Alport syndrome (XLAS) is a congenital renal disease caused by mutations in COL4A5. In XLAS cases suspected of being caused by aberrant splicing, transcript analysis needs to be conducted to determine splicing patterns and assess the pathogenicity. It has been reported that 13.7% or 14.9% of pathogenic COL4A5 mutations are splice site mutations[2,3] In these previous studies, no intronic variants leading to aberrant COL4A5 splicing outside of the consensus sequence (AG-GT) were identified. Diagnosed XLAS cases lacking COL4A5 exonic or consensus splice site variants can be caused by intronic or synonymous exonic splicing abnormalities. The most reliable method to identify splicing aberrations is by in vivo assay This method is based on the analysis of mRNA derived from the affected tissue. The best approach to identify splicing mutations with a role in disease is to use a combination of these in vivo, in silico and in vitro analyses[7]
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