Premium
Identification of novel germline mutations in the VHL gene in Hungarian von Hippel‐Lindau patients
Author(s) -
LOSONCZY G,
FAZAKAS F,
PFLIEGLER G,
KOMAROMI I,
BERTA A
Publication year - 2011
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2011.2225.x
Subject(s) - von hippel–lindau disease , missense mutation , hemangioblastoma , germline mutation , pheochromocytoma , germline , renal cell carcinoma , genetics , medicine , mutation , cancer research , folliculin , biology , pathology , disease , gene
Purpose Von Hippel‐Lindau disease is an autosomal dominantly inherited highly penetrant tumor syndrome predisposing to retinal and central nervous system hemangioblastomas, renal cell carcinoma and pheochromocytoma among other less frequent complications. Our goal was to establish genotype‐phenotype correlation in Hungarian von Hippel‐Lindau patients. Methods Fourteen members (9 patients and 5 healthy family members) of 6 unrelated families with type 1 VHL disease underwent clinical and molecular genetic examination. The effect of a novel missense mutation was predicted using molecular modeling. Results Retinal angioma was detected in seven patients; six patients had central nervous system hemangioblastoma and three patients developed RCC. Molecular genetic investigations detected four novel (c.232A>T, c.340+1G>A, c.163G>T, c.555C>A) and two previously described (c.583C>T and c.472C>G) germline mutations in the VHL gene, including four mutations leading to protein truncation and two missense mutations. Conclusion RCC only associated to MLTP among our patients, in accordance with previous findings. The novel c.163G>T mutation associated to bilateral RCC and retinal angioma in a 15‐years‐old male patient, which is the earliest occurrence of RCC in VHL disease reported so far. Molecular modeling of the VHL‐Elongin C complex predicted that the c.232A>T mutation responsible for the p.Asn78Tyr amino acid exchange remarkably changes the 77‐83 loop structure of the VHL protein destabilizing the VHL protein and the VHL‐ Elongin C complex. Therefore it is predicted to cause type I phenotype, as seen in our patient indeed. Our results can be useful for genetic counseling and follow‐up of VHL patients.