Germline VHL gene mutations in Hungarian families with von Hippel–Lindau disease and patients with apparently sporadic unilateral pheochromocytomas

Abstract

Objective: Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome caused by mutations or deletions of the VHL tumor-suppressor gene. Germline VHL gene alterations may be also present in patients with apparently sporadic pheochromocytoma (ASP), although a wide variation in mutation frequencies has been reported in different patient cohorts. Design: Herein, we report the analysis of the VHL gene in Hungarian families with VHL disease and in those with ASP. Methods: Seven families (35 members) with VHL disease and 37 unrelated patients with unilateral ASP were analyzed. Patients were clinically evaluated and the VHL gene was analyzed using direct sequencing, multiplex ligation-dependent probe amplification, and real-time PCR with SYBR Green chemistry. Results: Disease-causing genetic abnormalities were identified in each of the seven VHL families and in 3 out of the 37 patients with ASP (one nonsense and six missense mutations, two large gene deletions and one novel 2 bp deletion). Large gene deletions and other genetic alterations resulting in truncated VHL protein were found only in families with VHL type 1, whereas missense mutations were associated mainly, although not exclusively, with VHL type 2B and type 2C. Conclusions: The spectrum of VHL gene abnormalities in the Hungarian population is similar to that observed in Western, Japanese, or Chinese VHL kindreds. The presence of VHL gene mutations in 3 out of the 37 patients with ASP suggests that genetic testing is useful not only in patients with VHL disease but also in those with ASP.

MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

“…13,14 Pheochromocytomas were only regarded as sporadic benign or sporadic recurring, if germ-line mutation in any candidate pheochromocytoma gene has been excluded. The diagnosis of neurofibromatosis type 1 was excluded by clinical examination.…”

Molekuláris genetikai vizsgálatok az örökletes endokrinológiai tumor szindrómák klinikai diagnosztikájában

“…A teljes kódoló szakasz PCR-t követő Sanger-szekvená-lással és MLPA-val *új generációs szekvenálással, validált génpanelek bevezetése indokolt AIP = aryl interacting protein; CDC73 = ciklindependenskináz-73; CDKN1B = ciklinfüggőkináz-inhibitor-1B; FH = fumarát-hidratáz; GCM2 = gliasejt hiányzó homológ-2; GOT2 = glutamin-oxálecetsav-transzamináz; KIF1B = a kinezincsalád 1B-tagja; MAX = MYC-hez kapcsolódó faktor-X; MDH2 = malát-dehidrogenáz-2; MLPA = multiplex ligatióspróba-amplifikáció; MTC = medullaris pajzsmirigyrák; NF1 = neurofibromatosis 1-es típusa; PHD2 = propil-hidroxiláz-domént tartalmazó fehérje-2; PTEN = foszfatáz-és tenzinhomológ; RET = transzfekció során újraszerve-ződő fehérje; SDHA = szukcinát-dehidrogenáz A-alegysége; SDHAF2 = szukcinát-dehidrogenáz AF2-alegysége; SDHB = szukcinát-dehidrogenáz B-alegysége; SDHC = szukcinát-dehidrogenáz C-alegysége; SDHD = szukcinát-dehidrogenáz D-alegysége; TMEM127 = transzmembrán-protein-127; VHL = von Hippel-Lindau csoportba, amelyhez szükséges MLPA-vagy valamilyen egyéb, géndózis kimutatására alkalmas módszer [22,23].…”

“…A hazai VHL-gén-eltérésekhez társuló klinikai manifesztációk ismertetésével kimutattuk, hogy az MLPAvizsgálat a hazai beteganyagban is mintegy 15%-kal nö-velte a genetikai pozitív esetek számát [22], valamint a Ser80Leu-génvariáns patogenitását is egy nagy létszámú család részletes feldolgozásával bizonyítottuk [21].…”

Von Hippel-Lindau Disease: A Genetic and Clinical Review

“…23 In 2010, a study in the Netherlands 24 analyzed mutations in 945 VHL families and found VHL type 1 families to have 43% missense mutations, 17% frameshift mutations, 13% nonsense, 9% splice, 8% inframe deletion/insertions, and 10% partial/complete deletions. Partial large gene deletions result in complete defect of protein function.…”

“…Partial large gene deletions result in complete defect of protein function. 11,23 In contrast, VHL type 2 is more likely associated with missense mutations affecting the protein-binding sites of the VHL protein. 11,23 This mutation was also found in the Netherlands family study where missense mutations were found in 83.5% of VHL type 2 families.…”