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Article Dans Une Revue Blood Année : 2018

Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease

1 CRCINA-ÉQUIPE 16 - Molecular Mechanisms of Chronic Inflammation in Hematological Diseases
2 ITX - ITX - unité de recherche de l'institut du thorax
3 Universität Ulm - Ulm University [Ulm, Allemagne]
4 Institute for Clinical Transfusion Medicine and Immunogenetics [Ulm, Germany]
5 University of Oxford
6 Oxford NIHR Biomedical Research Centre
7 IGDR - Institut de Génétique et Développement de Rennes
8 UNIFR - Université de Fribourg = University of Fribourg
9 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
10 HEGP - Hôpital Européen Georges Pompidou [APHP]
11 UPD5 - Université Paris Descartes - Paris 5
12 UMR 1186 - Immunologie intégrative des tumeurs
13 IGR - Institut Gustave Roussy
14 Service de génétique médicale - Unité de génétique clinique [Nantes]
15 CIT - (le programme) Cartes d'identité des tumeurs
16 ITX-lab - ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291
17 Oxford University Hospitals NHS Trust
18 PREDIR - Centre de Références Cancers Rares
19 Hôpital Bicêtre
20 UP11 UFR Médecine - Université Paris-Sud - Paris 11 - Faculté de médecine
21 APHP - Hôpitaux Universitaires Paris-Sud Bicêtre
22 Hôpital Necker - Enfants Malades [AP-HP]
23 MARHEA - Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker]
24 Service de neurochirurgie pédiatrique [CHU Necker]
25 USPC - Université Sorbonne Paris Cité
26 DUTH - Democritus University of Thrace
27 Universitätsklinikum Ulm - University Hospital of Ulm
28 CHU Nantes - Centre Hospitalier Universitaire de Nantes
29 Université Paris-Saclay
30 NHCS - National Heart Centre Singapore
31 Service d'hématologie biologique [CHU de Dijon]
32 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
33 laboratory of Excellence GR-Ex, Paris, France
34 Unipd - Università degli Studi di Padova = University of Padua
35 C.H.U. Sart Tilman [Liège]
36 University Medical Center [Utrecht]
37 AöR - University Hospital Essen
38 NKUA - National and Kapodistrian University of Athens
39 Cliniques Universitaires Saint-Luc [Bruxelles]
40 Centro Hospitalar e Universitário [Coimbra]
Maria-Luigia Randi
  • Fonction : Auteur

Résumé

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 von Hippel-Lindau disease, which is characterized by the development of highly vascularized tumors. Here, we identified a new VHL cryptic-exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identified mutations in E1' in seven families with erythrocytosis (one homozygous case and six compound-heterozygous cases with a mutation in E1' in addition to a mutation in VHL coding sequences) and in one large family with typical VHL disease but without any alteration in the other VHL exons. In this study we have shown that the mutations induced a dysregulation of the VHL splicing with excessive retention of E1' and are associated with a downregulation of VHL protein expression. In addition, we have demonstrated a pathogenic role for synonymous mutations in VHL-Exon 2 that alter splicing through E2-skipping in five families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially impact splicing, correlating with phenotype severity. This study demonstrates that cryptic-exon-retention or 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 into the VHL-related-hypoxia-signaling pathway.
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Dates et versions

hal-01833917 , version 1 (13-07-2018)

Identifiants

Citer

Marion Lenglet, Florence Robriquet, Klaus Schwarz, Carme Camps, Anne Couturier, et al.. Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease. Blood, 2018, 132 (5), pp.469-483. ⟨10.1182/blood-2018-03-838235⟩. ⟨hal-01833917⟩
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