This report describes von Hippel-Lindau syndrome (VHL syndrome), which exhibits autosomal dominant inheritance. The human gene implicated in this disease is VHL (Von Hippel-Lindau Tumor Suppressor, E3 Ubiquitin Protein Ligase); the VHL gene is also implicated in several other human diseases (see MIM:608537). There is a single fly ortholog, Dmel\Vhl, for which an amorphic allele created by targeted recombination, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Vhl is a lower-scoring ortholog of a related human gene, VHLL.
UAS constructs of the human Hsap\VHL gene have been introduced into flies, including wild-type and variants implicated in human disease. Partial heterologous rescue (functional complementation) has been demonstrated: ubiquitous expression of the human gene partially rescues the lethal phenotype of an amorphic allele of Dmel\Vhl.
Variant(s) implicated in human disease tested (as transgenic human gene, VHL): the N78S, Y98H, F119L, and F136L variant forms of the human gene has been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R132Q in the fly Vhl gene (corresponds to R167Q in the human VHL gene); Y51H in the fly Vhl gene (corresponds to Y98H in the human VHL gene); the frameshift mutation E58fs in the fly Vhl gene (corresponds to E55fs in the human VHL gene).
The amorphic mutation of Dmel\Vhl causes lethality in the first larval instar; tracheal defects are observed. Transgenic constructs carrying mutations analogous to disease-implicated variants in human have been generated (see above). Physical and genetic interactions of Dmel\Vhl have been described; see below and in the gene report for Vhl.
[updated Feb. 2020 by FlyBase; FBrf0222196]
[VON HIPPEL-LINDAU SYNDROME; VHLS](https://omim.org/entry/193300)
[VON HIPPEL-LINDAU TUMOR SUPPRESSOR; VHL](https://omim.org/entry/608537)
[CYCLIN D1; CCND1](https://omim.org/entry/168461)
VHL is characterized by the abnormal growth of blood vessels in certain parts of the body (angiomatosis or hemangioblastomas), which may be benign. Benign tumors and cysts that press on nerves and brain tissue may develop, causing neurological symptoms. Retinal hemangioblastomas occur in approximately 70% of individuals with VHL, affecting vision. Malignant growths in the kidneys (renal cell carcinoma) develop in approximately 40% of affected individuals and are a leading cause of death from this condition. [from NORD, Von Hippel-Lindau Syndrome; 2016.02.15]
Von Hippel-Lindau syndrome (VHL) is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors. [from MIM:193300; 2016.02.15]
Von Hippel-Lindau syndrome is inherited as a heterozygous mutation in the VHL gene. [from MIM:193300; 2016.02.15] Evidence supports the hypothesis that the VHL gene functions as a recessive tumor suppressor gene and that inactivation of both alleles of the VHL gene is a critical event in the pathogenesis of VHL neoplasms (Crossey et al., 1994; pubmed:8270255). [from MIM:608537; 2016.02.15]
The VHL protein is an E3 ubiquitin protein ligase that functions as part of the the von Hippel-Lindau ubiquitination complex (VCB-CUL2 complex); one of the known targets of this complex is hydroxylated hypoxia-inducible factor (HIF). [from Gene Cards, VHL Gene; 2016.02.15]
