First estimate of the scale of canonical 5′ splice site GT>GC variants capable of generating wild‐type transcripts

Autor: Matthew Mort, Gérald Le Gac, Jin-Huan Lin, Shun-Jiang Deng, Chandran Ka, David N. Cooper, Wen-Bin Zou, Yann Fichou, Arnaud Boulling, Emmanuelle Masson, Jian-Min Chen, Isabelle Berlivet, Matthew J. Hayden, Zhuan Liao, Xin-Ying Tang, Loann Raud, Raphaël Leman, Marlène Le Tertre, Zhao-Shen Li, Claude Férec, Claude Houdayer
Přispěvatelé: INSERM U1078, Université de Brest (UBO), Etablissement Français du Sang Bretagne, EFS, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Medical Genetics, College of Medicine, Cardiff University, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institute of Medical Genetics, Cardiff University-School of Medicine, Shanghai Institute of Pancreatic Diseases, Shanghai, China, Shanghai Institute of Pancreatic Diseases, BOULLING, Arnaud, EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Second Military Medical University [Shanghai], Shanghai Institute of Pancreatic Diseases [Shanghai, China], Hôpital Morvan - CHRU de Brest (CHU - BREST ), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
full-length gene splicing assay
[SDV]Life Sciences [q-bio]
Gene splicing
human inherited disease
noncanonical splice donor site
canonical 5′ splice site
Biology
genotype and phenotype relationship
03 medical and health sciences
Human disease
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Genomics [q-bio.GN]
Genetics
Humans
Position-Specific Scoring Matrices
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Nucleotide Motifs
Clinical phenotype
Gene
Cells
Cultured
ComputingMilieux_MISCELLANEOUS
Genetics (clinical)
030304 developmental biology
0303 health sciences
[SDV.GEN]Life Sciences [q-bio]/Genetics
Base Sequence
Gene Expression Profiling
030305 genetics & heredity
Wild type
Computational Biology
Genetic Variation
High-Throughput Nucleotide Sequencing
Exons
Sequence Analysis
DNA
Introns
[SDV] Life Sciences [q-bio]
Alternative Splicing
Gene Expression Regulation
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Cell culture
RNA splicing
[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Genomics [q-bio.GN]
RNA Splice Sites
Databases
Nucleic Acid
human gene mutation database
Small nuclear RNA
Zdroj: Human Mutation
Human Mutation, Wiley, 2019, 40 (10), pp.1856-1873. ⟨10.1002/humu.23821⟩
ISSN: 1059-7794
1098-1004
DOI: 10.1002/humu.23821⟩
Popis: International audience; It has long been known that canonical 5' splice site (5'SS) GT>GC variants may be compatible with normal splicing. However, to date, the actual scale of canonical 5'SSs capable of generating wild-type transcripts in the case of GT>GC substitutions remains unknown. Herein, combining data derived from a meta-analysis of 45 human disease-causing 5'SS GT>GC variants and a cell culture-based full-length gene splicing assay of 103 5'SS GT>GC substitutions, we estimate that ~15-18% of canonical GT 5'SSs retain their capacity to generate between 1% and 84% normal transcripts when GT is substituted by GC. We further demonstrate that the canonical 5'SSs in which substitution of GT by GC-generated normal transcripts exhibit stronger complementarity to the 5' end of U1 snRNA than those sites whose substitutions of GT by GC did not lead to the generation of normal transcripts. We also observed a correlation between the generation of wild-type transcripts and a milder than expected clinical phenotype but found that none of the available splicing prediction tools were capable of reliably distinguishing 5'SS GT>GC variants that generated wild-type transcripts from those that did not. Our findings imply that 5'SS GT>GC variants in human disease genes may not invariably be pathogenic.
Databáze: OpenAIRE
Externí odkaz: