published in Blood: New lessons from an old gene: complex splicing and a novel cryptic exon in VHL gene cause erythrocytosis and VHL disease

Article from Yannick ARLOT'S team "Molecular bases of tumorigenesis: VHL disease"


New lessons from an old gene: complex splicing and a novel cryptic exon in VHL gene cause erythrocytosis and VHL disease .

Lenglet M1,2,3, Robriquet F2,3, Schwarz K4,5, Camps C6,7, Couturier A8, Hoogewijs D9, Buffet A10,11,12, Knight SJL6,7, Gad S1,13, Couvé S1,13, Chesnel F8, Pacault M2,14, Lindenbaum P3, Job S15, Dumont S2, Besnard T3,14, Cornec M3, Dreau H16, Pentony M6,7, Kvikstad E6,7, Deveaux S17,18,19,20, Burnichon N10,11,12,18,19,21, Ferlicot S17,22, Vilaine M2, Mazzella JM10,11,12,18,19,21, Airaud F14, Garrec C14, Heidet L23, Irtan S24, Mantadakis E25, Bouchireb K23, Debatin KM26, Redon R3, Bezieau S3,14, Bressac-de Paillerets B13,27, Teh BT28, Girodon F29,30,31, Randi ML32, Putti MC33, Bours V34, Van Wijk R35, Göthert JR36, Kattamis A37, Janin N38, Bento C39, Taylor JC6,7, Arlot-Bonnemains Y8, Richard S1,13,17,18,19,20, Gimenez-Roqueplo AP10,11,12,18,19,21, Cario H26, Gardie B1,2,3,31.

2018 Aug 2;132(5):469-483. doi: 10.1182/blood-2018-03-838235. Epub 2018 Jun 11.


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 E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1' in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1' 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 E1' 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.

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