An 11-bp duplication in the promoter region of the VHL gene in a patient with cerebellar hemangioblastoma and renal oncocytoma.
Central nervous system hemangioblastomas are benign vascular tumours that may present sporadically or as manifestation of the von Hippel-Lindau (VHL) disease. VHL Syndrome is a rare autosomal dominant disorder characterized, besides hemangioblastomas, by susceptibility to multifocal and bilateral renal cell carcinoma and cysts, retinal angiomas, pheochromocytoma, epididymis cystoadenoma, pancreatic cysts and/or islet cell tumours. Germline mutations of VHL tumour suppressor gene cause the VHL disease, while somatic mutations have been associated with sporadic hemangioblastomas and clear-cell renal carcinomas. We identified an 11-bp duplication in the promoter region of the VHL gene in a VHL-affected individual. Functional analysis revealed that this variant affects the binding or the binding affinity of one or more transcription factors that regulate the transcription of VHL in vivo, reducing the endogenous levels of VHL mRNA. Moreover, consistent with the "two hits" model, microsatellite analysis of hemangioblastoma tissue from this patient revealed Allelic Imbalance for the chromosomal region near the VHL gene. We propose that these molecular events, through a loss of pVHL function, lead to the onset of the VHL-related tumours in that individual.
Muscarella
Lucia Anna
LA
Servizio Genetica Medica, IRCCS "Casa Sollievo della Sofferenza", Poliambulatorio "Giovanni Paolo II, Viale Padre Pio, 71013, San Giovanni Rotondo, Italy.
Barbano
Raffaela
R
Servizio Genetica Medica, IRCCS "Casa Sollievo della Sofferenza", Poliambulatorio "Giovanni Paolo II, Viale Padre Pio, 71013, San Giovanni Rotondo, Italy.
Augello
Bartolomeo
B
Servizio Genetica Medica, IRCCS "Casa Sollievo della Sofferenza", Poliambulatorio "Giovanni Paolo II, Viale Padre Pio, 71013, San Giovanni Rotondo, Italy.
Formica
Vincenza
V
Servizio Genetica Medica, IRCCS "Casa Sollievo della Sofferenza", Poliambulatorio "Giovanni Paolo II, Viale Padre Pio, 71013, San Giovanni Rotondo, Italy.
Micale
Lucia
L
Servizio Genetica Medica, IRCCS "Casa Sollievo della Sofferenza", Poliambulatorio "Giovanni Paolo II, Viale Padre Pio, 71013, San Giovanni Rotondo, Italy.
Zelante
Leopoldo
L
Servizio Genetica Medica, IRCCS "Casa Sollievo della Sofferenza", Poliambulatorio "Giovanni Paolo II, Viale Padre Pio, 71013, San Giovanni Rotondo, Italy.
D'Agruma
Leonardo
L
Servizio Genetica Medica, IRCCS "Casa Sollievo della Sofferenza", Poliambulatorio "Giovanni Paolo II, Viale Padre Pio, 71013, San Giovanni Rotondo, Italy.
Merla
Giuseppe
G
Servizio Genetica Medica, IRCCS "Casa Sollievo della Sofferenza", Poliambulatorio "Giovanni Paolo II, Viale Padre Pio, 71013, San Giovanni Rotondo, Italy. g.merla@operapadrepio.it.
D018249:Adenoma, Oxyphilic / Q000235:genetics*; D000328:Adult; D022981:Allelic Imbalance; D001483:Base Sequence; D002528:Cerebellar Neoplasms / Q000209:etiology / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D018325:Hemangioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007680:Kidney Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000473:pathology
D051794:Von Hippel-Lindau Tumor Suppressor Protein