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• Disease gene identification
• Alternative RNA processing

Brief research history:

In the 1990’s, he contributed to the identification of important disease genes by positional cloning (examples in ref. 1-4). For example, he successfully used selection of complementary DNA by yeast artificial chromosomes that carried large pieces of human chromosome X to identify a gene for Bruton’s disease (1-3), immunodeficiency characterized by a lack of mature B cells and immunoglobulins and susceptibility to bacterial infections (5). These breakthrough studies led to a surge of functional investigations of newly identified proteins before the genome sequence became available and permitted molecular diagnostics of many diseases, including inherited cancer syndromes (6-7).

Later, he became interested in regulation of RNA processing, particularly gene splicing, with a plethora of publications studying the role of numerous splicing factors in this process. His group also investigated the impact of natural DNA variants, transposed elements and divalent metals on the splicing code, which controls cellular decisions if to remove intervening sequences from primary gene transcripts or not (8-12). As the Emeritus Fellow, he is still research active in this field (13).

Selected

1. Vorechovsky, I. et al. Isolation of cDNA clones mapping around DXS178: a search for human X-linked agammaglobulinaemia gene using yeast artificial chromosomes, cosmids and direct cDNA selection. Immunodeficiency 4, 221-224 (1993).
2. Vetrie, D., Vorechovsky, I., et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361, 226-233 (1993).
3. Thomas, J.D. et al. Co-localization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science 261, 355-358 (1993).
4. Hahn, H. et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841-851 (1996).
5. Bruton, O.C. Agammaglobulinemia. Pediatrics, 9, 722, 1952.
6. Vorechovsky, I. et al. Molecular diagnosis of X-linked agammaglobulinaemia. Lancet 341, 1153 (1993).
7. Vorechovsky, I., et al. Trichoepitheliomas contain somatic mutations in the overexpressed PTCH gene: support for a gatekeeper mechanism in skin tumorigenesis. Cancer Res 57, 4677-4681 (1997).
8. Kralovicova, J. et al. Branch site haplotypes that control alternative splicing. Hum Mol Genet 13, 3189-3202 (2004).
9. Kralovicova, J. et al. Restriction of an intron size en route to endothermy. Nucleic Acids Res 49, 2460-2487 (2021).
10. Pengelly, R. et al.. Exonic splicing code and protein binding sites for calcium. Nucleic Acids Res 50, 5493-5512 (2022).
11. Vorechovsky, I. Transposable elements in disease-associated cryptic exons. Hum Genet 127, 135-154 (2010).
12. Borovska, I. et al. Alu RNA fold links splicing with signal recognition particle proteins. Nucleic Acids Res 51, 8199-8216 (2023).
13. Vorechovsky, I. From benign to pathogenic variants and vice versa: pyrimidine transitions at position -3 of TAG and CAG 3' splice sites. J Hum Genet 70, 125-133 (2025).