Basal exon skipping and genetic pleiotropy: A predictive model of disease pathogenesis

Abstract

Genetic pleiotropy, the phenomenon by which mutations in the same gene result in markedly different disease phenotypes, has proven difficult to explain with traditional models of disease pathogenesis. We have developed a model of pleiotropic disease that explains, through the process of basal exon skipping, how different mutations in the same gene can differentially affect protein production, with the total amount of protein produced correlating with disease severity. Mutations in the centrosomal protein of 290 kDa (CEP290) gene are associated with a spectrum of phenotypically distinct human diseases (the ciliopathies). Molecular biologic examination of CEP290 transcript and protein expression in cells from patients carrying CEP290 mutations, measured by quantitative polymerase chain reaction and Western blotting, correlated with disease severity and corroborated our model. We show that basal exon skipping may be the mechanism underlying the disease pleiotropy caused by CEP290 mutations. Applying our model to a different disease gene, CC2D2A (coiled-coil and C2 domains–containing protein 2A), we found that the same correlations held true. Our model explains the phenotypic diversity of two different inherited ciliopathies and may establish a new model for the pathogenesis of other pleiotropic human diseases.

Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies

“…Alternatively, AONs can be employed to skip (combinations of) exons that contain nonsense or frame-shift mutations, taking into account to leave the reading-frame intact, or to restore the reading-frame in case this is disrupted by large deletions encompassing one or more exons. This may particularly be beneficial for larger genes, as the shortened protein that results from exon skipping should still have some residual function as recently shown in CEP290-associated LCA (Drivas et al 2015;Rozet and Gerard 2015). A third therapeutic approach involves restoring normal splicing in case exonic mutations activate cryptic splice sites within the exon.…”

Homozygous knockout of the piezo1 gene in the zebrafish is not associated with anemia

“…Basal exon-skipping has been proposed to be a widespread mechanism for generation of genetic pleiotropy, active even in the absence of frameshift and termination mutations. 15 Thus, the mRNA transcript of the ZFN-knockout allele might undergo exon-skipping between exon 8 and a locus between exons 22 and 42, but the resulting large internal deletion probably would not encode a functional PIEZO1 polypeptide. Alternatively, piezo1 mRNA translation might undergo re-initiation at a downstream initiation codon, such as M438 in exon 11 (corresponding to mPIEZO1 L424), or at a methionine further downstream, or at an atypical translational re-initiation codon.…”

The expanding phenotypic spectra of kidney diseases: insights from genetic studies

“…2). This mechanism of basal exon skipping is expected to extend beyond ciliopathies and apply to other diseases with considerable phenotypic heterogeneity as well 60 . In addition to variations in the degree of protein impairment, genetic modifiers, such as heterozygous mutations in TTC21B 51 , also contribute to phenotypic heterogeneity in ciliopathies 62 .…”