Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe |
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| Authors: | Damjan Glava? Hartmut P H Neumann Claudia Wittke Hendrik Jaenig Otakar Ma?ek Teodor Streicher Friederike Pausch Dieter Engelhardt Karl H Plate Heinz Höfler Fan Chen Berton Zbar Hiltrud Brauch |
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| Institution: | (1) Institute of Pathology, Laboratory of Molecular Pathology, Technical University Munich, Trogerstrasse 32, D-81675 Munich, Germany, DE;(2) Institute of Pathology, Laboratory of Molecular Pathology, Medical Faculty, Korytkova 2, SI-61115 Ljubljana, Slovenia,;(3) Department of Medicine, Division of Nephrology and Hypertension, Albert Ludwigs University Freiburg, D-79106 Freiburg, Germany, DE;(4) Zlin Hospital, CZ-76275 Zlin, Czech Republic,;(5) Boynice Hospital, SK-97201Bojnice, Republic Slovakia,;(6) Department of Medicine, Division of Endocrinology, Ludwig Maximilians University Munich, Machioninistrasse 15, D-81366 München-Grosshadern, Germany, DE;(7) Neurocenter, Department of Neuropathology, Albert Ludwigs University Freiburg, D-79106 Freiburg, Germany, DE;(8) Program Resources, Science Application International Corp, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702–1201, USA, US;(9) Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21701–1201, USA, US;(10) Laboratory of Oncology, University Womans Clinic Eppendorf, Martinistrasse 52, D-20246 Hamburg Tel.: +49-40-4717-2558; Fax: +49-40-4717-4103, OM |
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| Abstract: | von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome predisposing to retinal, cerebellar and
spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma and pancreatic tumors. Clinically two types of the disease
can be distinguished: VHL type 1 (without pheochromocytoma) and VHL type 2 (with pheochromocytoma). We report VHL germline mutations and trends in phenotypic variation in families from central Europe. We identified 28 mutations in 53/65
(81.5%) families with 18 (64%) mutations being unique to this population. Whereas types and distribution of mutations as well
as a strong correlation of missense mutations with the VHL 2 phenotype were similar to those identified in other populations,
these families have provided new insights into the molecular basis for variability in the VHL 2 phenotype. Seven different
missense mutations in exons 1 and 3 varied in their biological consequences from a minimal VHL 2 phenotype with pheochromocytoma
only to a full VHL 2 phenotype with RCC and pancreatic lesion. These findings contribute to a better understanding of the
fundamental mechanisms of VHL disease and its phenotypic variability. Further, we have provided rapid VHL screening for the families in central Europe, which has resulted in improved diagnosis and clinical management.
Received: 10 November 1995 / Revised: 1 March 1996 |
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