Refining clinically relevant parameters for mis-splicing risk in shortened introns with donor-to-branchpoint space constraint.

Autor: Zhang KY; Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Functional Neuromics, Children's Medical Research Institute, Westmead, NSW, Australia.; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia., Joshi H; Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Functional Neuromics, Children's Medical Research Institute, Westmead, NSW, Australia., Marchant RG; Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Functional Neuromics, Children's Medical Research Institute, Westmead, NSW, Australia.; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia., Bryen SJ; Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Functional Neuromics, Children's Medical Research Institute, Westmead, NSW, Australia.; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia.; Centre for Population Genomics, Garvan Institute of Medical Research, UNSW & Murdoch Children's Research Institute, Sydney & Melbourne, Australia., Dawes R; Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Functional Neuromics, Children's Medical Research Institute, Westmead, NSW, Australia.; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia.; Big Data Institute and Centre for Human Genetics, University of Oxford, Oxford, UK., Yuen M; Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Functional Neuromics, Children's Medical Research Institute, Westmead, NSW, Australia.; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia., Cooper ST; Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Functional Neuromics, Children's Medical Research Institute, Westmead, NSW, Australia.; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia., Evesson FJ; Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Westmead, NSW, Australia. frances.evesson@sydney.edu.au.; Functional Neuromics, Children's Medical Research Institute, Westmead, NSW, Australia. frances.evesson@sydney.edu.au.; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. frances.evesson@sydney.edu.au.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Aug; Vol. 32 (8), pp. 972-979. Date of Electronic Publication: 2024 May 27.
DOI: 10.1038/s41431-024-01632-9
Abstrakt: Intronic deletions that critically shorten donor-to-branchpoint (D-BP) distance of a precursor mRNA impose biophysical space constraint on assembly of the U1/U2 spliceosomal complex, leading to canonical splicing failure. Here we use a series of β-globin (HBB) gene constructs with intron 1 deletions to define D-BP lengths that present low/no risk of mis-splicing and lengths which are critically short and likely elicit clinically relevant mis-splicing. We extend our previous observation in EMD intron 5 of 46 nt as the minimal productive D-BP length, demonstrating spliceosome assembly constraint persists at D-BP lengths of 47-56 nt. We exploit the common HBB exon 1 β-thalassemia variant that strengthens a cryptic donor (NM_000518.5(HBB):c.79G > A) to provide a simple barometer for the earliest signs of space constraint, via cryptic donor activation. For clinical evaluation of intronic deletions, we assert D-BP lengths > 60 nt present low mis-splicing risk while space constraint increases exponentially with D-BP lengths < 55 nt, with critical risk and profound splicing abnormalities with D-BP lengths < 50 nt.
(© 2024. The Author(s).)
Databáze: MEDLINE
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