Abstract
Background
von Hippel–Lindau disease (VHL), also called angiomatosis retinae, is inherited as an autosomal dominant trait. It is frequently associated with other tumors in the central nervous system, kidneys, or adrenal glands. In order to investigate the relationship between genotype and corresponding phenotypes, we performed molecular genetic analysis in a Japanese patient with VHL type 2A.
Methods
After informed consent had been obtained, the three exons of the VHL gene were PCR-amplified and sequenced either directly or after subcloning. Clinical features were also examined.
Results
A novel in-frame duplication of the 21 base pairs at nucleotide 806 (the position of codon 198) of the VHL gene was found in our patient. The clinical phenotype of the patient included retinal hemangiomas associated with vitreous hemorrhage and traction retinal detachment, pheochromocytoma, and hemangioma-like lesions in the cerebellum which corresponded to those of VHL type 2A. Abnormal diffuse vascular leakage was observed in the apparently intact retina by fluorescein angiography.
Conclusion
An insertion mutation of the VHL gene is a rare association with VHL type 2. This insertion mutation may interfere the binding between the VHL gene and elongins. Abnormal retinal vascular leakage suggests the possible effects of overexpressed vascular permeability factors such as vascular endothelial growth factor from hemangiomas associated with defective VHL gene.
References
Chan CC, Vortmeyer AO, Chew EY, et al (1999) VHL gene deletion and enhanced VEGF gene expression detected in the stromal cells of retinal angioma. Arch Ophthalmol 117:625–630
Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA (1996) Negative regulation of hypoxia-inducible genes by the von Hippel–Lindau protein. Proc Natl Acad Sci USA 93:10595–10599
Kishida T, Stackhouse TM, Chen F, Lerman MI, Zbar B (1995) Cellular proteins that bind the von Hippel–Lindau disease gene product: mapping of binding domains and the effect of missense mutations. Cancer Res 55:4544–4548
Latif F, Tory K, Gnarra J, et al (1993) Identification of the von Hippel–Lindau disease suppressor gene. Science 260:1317–1320
Niemelä M, Lemeta S, Sainto M, et al (2000) Hemangioblastomas of the retina: impact of von Hippel–Lindau disease. Invest Ophthalmol Vis Sci 41:1909–1915
Zbar B, Kishida T, Chen F, et al (1996) Germline mutations in the von Hippel–Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 8:348–357
Acknowledgements
This study was supported in part by grants from Karoji Memorial Medical Research Funds, Hirosaki, Japan (Dr. Nakazawa); Grants-in-Aid for Scientific Research B-12557145 and B-11470361 (Dr. Nakazawa) from the Ministry of Education, Culture, Sports, Science, and Technology, Tokyo, Japan; and the the Research Committee on Chorioretinal Degenerations and Optic Atrophy, Ministry of Health, Welfare, and Labor, Tokyo, Japan (Dr. Nakazawa).
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Miyagawa, Y., Nakazawa, M., Noda, Y. et al. von Hippel–Lindau disease type 2A in a family with a duplicated 21-base-pair in-frame insertion mutation in the VHL gene. Graefe's Arch Clin Exp Ophthalmol 241, 241–244 (2003). https://doi.org/10.1007/s00417-003-0631-y
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DOI: https://doi.org/10.1007/s00417-003-0631-y