Browsing by Subject "Abnormal splicing"

Now showing 1 - 2 of 2
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    From bedside to genetic analysis: New insights into pathophysiology of melanoma, basal cell carcinoma, and other cancers
    (Wiley, 2024) Zemtsov, Alexander; Dermatology, School of Medicine
    Objective: Patients with myotonic muscular dystrophy (MMD) were observed to have numerous basal cell carcinoma (BCC) and abnormal dysplastic nevi (DN) on non-sun exposed skin. Simultaneously a large study published in the Journal of American Medical Association (JAMA) illustrated that patients with MMD have "overall" an increased risk for cancer development. Based on these findings, this author in 2010 postulated that dysregulation of RNA binding proteins (RBP), responsible for clinical manifestations of MMD, is also responsible for the development of BCC and melanoma. Methods: To report new research elucidating the etiology of melanoma, BCC, MMD-induced cancers, and potentially other environmentally induced malignancies. Results: Dysregulation of RBP induces aberrant mRNA splicing; recent data indicates that abnormal mRNA splicing not just plays a key role in the pathogenesis of melanoma but is a hallmark of essentially all human malignancies. Conclusion: The author's hypothesis is that ultraviolet (UV) radiation induces DNA damage in intronic regions of a variety of genes. Furthermore, these UV-induced abnormal DNA dimers, repeats and mutations interfere with normal mRNA splicing thus producing abnormal proteins. These abnormal proteins in turn activate oncogenic pathways such as hedgehog, MAP kinase, and WNT.
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    Identifying Novel Causes of X-Linked Heterotaxy
    (2024-05) Wells, John Robert; Ware, Stephanie M.; Firulli, Anthony B.; Kim, Il-Man; Landis, Benjamin J.
    Heterotaxy is a congenital disorder characterized by abnormal arrangement of formation of thoracic and abdominal organs due to errors in embryonic left-right patterning, affecting ~1 in 10,000 live births. These patients exhibit considerable phenotypic heterogeneity, with structural heart defects significantly contributing to poor outcomes. Variants in several genes can disrupt laterality, but ZIC3 variants, primarily identified through targeted sequencing of its coding region, are the only recognized cause of X-liked heterotaxy. This dissertation focuses on a heterotaxy pedigree with four affected males, demonstrating an X-linked inheritance. No coding variant in ZIC3 was identified, leaving the pedigree unsolved for over two decades. Initially, the family’s heterotaxy was hypothesized to be caused by a coding variant in a novel heterotaxy locus on the X chromosome. X-exome sequencing identified a missense variant in GPR101, a gene whose closest phylogenetic relative has been implicated in left-right asymmetry in zebrafish. However, subsequent findings from this study and other research groups suggests GPR101 does not regulate left-right patterning, making the hypothesized GPR101 variant unlikely to be disease-causative. The next hypothesis explored was a non-coding variant in ZIC3, undetected by X-exome sequencing. Whole genome sequencing identified a novel, deep intronic variant in ZIC3, initially hypothesized to trigger the inclusion of an intronic sequence as a pseudoexon during RNA splicing. Further analysis revealed the variant profoundly altered RNA splicing, resulting in the production of several novel ZIC3 isoforms and reduced expression of normal ZIC3 protein. These novel isoforms displayed abnormal function in a variety of in vitro and in vivo assays. This marks the first reported instance of pseudoexon inclusion associated with heterotaxy for any gene and underscores the critical need to expand the scope of variant evaluation beyond mere missense and nonsense variants. The clinical and research field must adapt to assess non-coding variants and to consider alternative disease mechanisms, such as abnormal splicing or dysregulated expression of key left-right patterning genes, in unresolved heterotaxy cases.