Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis

Abstract

The von Hippel-Lindau (VHL) disease product is thought to down-regulate transcription by antagonizing elongin-enhanced transcriptional elongation. Germline VHL gene mutations predispose to the development of retinal, cerebellar and spinal haemangioblastomas, renal cell carcinoma and phaeochromocytoma. In addition, somatic Inactivation of the VHL gene is frequent in sporadic renal cell carcinoma and haemangioblastoma. Regulation of transcript elongation is an important control mechanism for gene expression and the VHL gene might modify the expression of proto-oncogenes and growth suppressor genes during embryogenesis. We therefore investigated the expression of VHL mRNA during human embryogenesis by in situ hybridization studies at 4, 6 and 10 weeks post conception. Although VHL mRNA was expressed in all three germ layers, strong expression was noted in the central nervous system, kidneys, testis and lung. Within the kidney, VHL mRNA was differentially expressed within renal tubules suggesting that the VHL gene product may have a specific role in kidney development. Two alternatively spliced VHL mRNAs characterized by inclusion (isoform I) or exclusion (isoform II) of exon 2 are transcribed in adult tissues. To investigate if the two isoforms are differentially expressed during embryogenesis, VHL mRNA was reverse transcribed from 13 fetal tissues (8-10 weeks gestation). The quantitative distribution of VHL mRNA within fetal tissues reflected that seen by in situ hybridization and the ratio of the two VHL isoforms was similar between tissues. Although the genes regulated by the VHL gene product have not yet been identified, our findings are compatible with the hypothesis that VHL-mediated control of transcriptional elongation may have a role in normal human development.

von Hippel–Lindau disease: A clinical and scientific review

“…4,40 The VHL mRNA and protein is widely expressed in both fetal and adult tissues. 41,42 VHL gene mutations have been reported in 4900 VHL disease kindreds, 6,43,44 (http://www.umd.be/VHL/W_VHL), but although a wide variety of mutations have been described, no unequivocal mutations have been reported in the first 53 amino acids of pVHL 30 . Germline VHL mutations are heterogeneous but the largest group, accounting for about 30-40% of cases, consists of deletions (ranging from 0.5 to 250 kb) that remove one or more VHL exons and usually arise from Alu-mediated recombination.…”

Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

“…The proportion of all PCCs and PGLs associated with each gene was estimated from genetic screenings (Amar et al 2005, Mannelli et al 2009, Yao et al 2010a,b, Korpershoek et al 2011 (Latif et al 1993). There are three VHL gene products: a full-length 213 amino acid protein and two shorter isoforms, resulting from an alternative splicing excluding the second exon and an alternative translation initiated from an in-frame ATG codon respectively (Richards et al 1996, Kaelin 2008. VHL is involved in oxygendependent regulation of hypoxia-inducible factor (HIF) by constituting a part of the E3 ubiquitin ligase complex that ubiquitinates HIF-1a, thereby targeting it for proteasomal degradation (Maynard & Ohh 2007, Kaelin 2008.…”

Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes

“…These primers and their optimal amplification conditions are summarized in Table 1. Previously described primer pairs were used for amplification of the P-actin (Horikoshi et al, 1992), VEGF (detecting VEGF121 165 189 ad 206 isoforms; Wizigmann-Voos et al, 1995), VHL and c-fos (Richards et al, 1996) genes. These primers also distinguish between cDNA and genomic DNA products.…”

“…Reintroduction of the wild-type VHL gene into VHL-null RCC cells suppresses the ability to form tumours in nude mice Iliopoulos et al, 1995). Although the VHL mRNA and protein are widely expressed, analysis of the differential expression of VHL mRNA in the kidney during human embryogenesis is compatible with a specific role in normal renal development (Richards et al, 1996). These findings suggest that the VHL gene would appear to be intimately involved in the control of growth and differentiation of normal renal tubular cells.…”