@article{3000695,
    title = "Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease",
    author = "Lenglet, M. and Robriquet, F. and Schwarz, K. and Camps, C. and Couturier, A. and Hoogewijs, D. and Buffet, A. and Knight, S.J.L. and Gad, S. and Couvé, S. and Chesnel, F. and Pacault, M. and Lindenbaum, P. and Job, S. and Dumont, S. and Besnard, T. and Cornec, M. and Dreau, H. and Pentony, M. and Kvikstad, E. and Deveaux, S. and Burnichon, N. and Ferlicot, S. and Vilaine, M. and Mazzella, J.-M. and Airaud, F. and Garrec, C. and Heidet, L. and Irtan, S. and Mantadakis, E. and Bouchireb, K. and Debatin, K.-M. and Redon, R. and Bezieau, S. and Brigitte Bressac-de, P. and Teh, B.T. and Girodon, F. and Randi, M.-L. and Putti, M.C. and Bours, V. and Van Wijk, R. and Göthert, J.R. and Kattamis, A. and Janin, N. and Bento, C. and Taylor, J.C. and Arlot-Bonnemains, Y. and Richard, S. and Gimenez-Roqueplo, A.-P. and Cario, H. and Gardie, B.",
    journal = "Blood advances",
    year = "2018",
    volume = "132",
    number = "5",
    pages = "469-483",
    publisher = "American Society of Hematology",
    doi = "10.1182/blood-2018-03-838235",
    keywords = "von Hippel Lindau protein;  VHL protein, human;  von Hippel Lindau protein, Article;  clinical article;  controlled study;  down regulation;  erythrocytosis;  exon;  exon skipping;  familial disease;  female;  gene expression;  gene identification;  gene mutation;  human;  human cell;  male;  pedigree;  priority journal;  protein expression;  RNA splicing;  von Hippel Lindau disease;  adolescent;  adult;  child;  classification;  genetic predisposition;  genetics;  heterozygote;  middle aged;  mutation;  pathology;  polycythemia;  RNA splicing;  von Hippel Lindau disease;  young adult, Adolescent;  Adult;  Child;  Exons;  Female;  Genetic Predisposition to Disease;  Heterozygote;  Humans;  Male;  Middle Aged;  Mutation;  Pedigree;  Polycythemia;  RNA Splicing;  von Hippel-Lindau Disease;  Von Hippel-Lindau Tumor Suppressor Protein;  Young Adult",
    abstract = "Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHL cryptic exon (termed E19) deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E19 in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E19 in addition to a mutation in VHL coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, we show that the mutations induced a dysregulation of VHL splicing with excessive retention of E19 and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHL exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway. © 2018 by The American Society of Hematology."
}