• Molecular basis of the VHL hereditary cancer syndrome.

• [From gene to disease; Von Hippel-Lindau disease]

• HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron.

• Intraoperative ultrasound aids in dissection during laparoscopic partial adrenalectomy.

• Clinical and genetic epidemiology of inherited renal disease in Newfoundland.

• Transcription factors in disease.

1
UI - 12209156
AU - Kaelin WG Jr
TI - Molecular basis of the VHL hereditary cancer syndrome.
SO - Nat Rev Cancer 2002 Sep;2(9):673-82
AD - Howard Hughes Medical Institute, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. william_kaelin@dfci.harvard.edu
The von Hippel-Lindau hereditary cancer syndrome was first described about 100 years ago. The unusual clinical features of this disorder predicted a role for the von Hippel-Lindau gene (VHL) in the oxygen-sensing pathway. Indeed, recent studies of this gene have helped to decipher how cells sense changes in oxygen availability, and have revealed a previously unappreciated role of prolyl hydroxylation in intracellular signalling. These studies, in turn, are laying the foundation for the treatment of a diverse set of disorders, including cancer, myocardial infarction and stroke.

2
UI - 12162174
AU - Hes FJ; Los M; van der Luijt RB
TI - [From gene to disease; Von Hippel-Lindau disease]
SO - Ned Tijdschr Geneeskd 2002 Jul 20;146(29):1364-7
AD - Leids Universitair Medisch Centrum, Klinisch-Genetisch Centrum Leiden, Postbus 9600, 2300 RC Leiden. f.j.hes@lumc.nl
Von Hippel-Lindau (VHL) disease is an autosomal, dominantly inherited, tumour syndrome. Carriers of a germline mutation in the VHL tumour suppressor genes are predisposed to develop tumours in various organs including the eye, cerebellum and kidney. These tumours are often multicentric or bilateral, and manifest at a younger age than in situations without a VHL germline mutation. VHL germline mutations are identified in virtually all families and sporadic patients with classic VHL disease. VHL associated tumours are richly vascularised. This is consistent with the involvement of the VHL protein in multiprotein complexes that degrade hypoxia-inducible factors dependent on cellular oxygen levels.

3
UI - 12124175
AU - Mandriota SJ; Turner KJ; Davies DR; Murray PG; Morgan NV; Sowter HM;
TI - Wykoff CC; Maher ER; Harris AL; Ratcliffe PJ; Maxwell PH HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron.
SO - Cancer Cell 2002 Jun;1(5):459-68
AD - Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom.
Mutations in the von Hippel-Lindau (VHL) gene are associated with hereditary and sporadic clear cell renal carcinoma. VHL acts in a ubiquitin ligase complex regulating hypoxia-inducible factor-1 (HIF-1), but the link between this function and cancer development is unclear. Here we show that in the kidneys of patients with VHL disease, HIF activation is an early event occurring in morphologically normal single cells within the renal tubules. In comparison, dysplastic lesions, cystic lesions, and tumors showed evidence of additional mechanisms that amplify HIF activation. Detection of cells with constitutive HIF activation identified a large number of previously unrecognized foci of VHL inactivation. In proximal tubules these were almost entirely unicellular, whereas multicellular foci were almost exclusively seen in the distal nephron.

4
UI - 12352391
AU - Pautler SE; Choyke PL; Pavlovich CP; Daryanani K; Walther MM
TI - Intraoperative ultrasound aids in dissection during laparoscopic partial adrenalectomy.
SO - J Urol 2002 Oct;168(4 Pt 1):1352-5
AD - Urological Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
PURPOSE: Adrenal cortical sparing surgery is a relatively new approach to adrenal tumors. Laparoscopic partial nephrectomy is a technically feasible but challenging operation. We describe the use of intraoperative ultrasound to facilitate laparoscopic partial nephrectomy in a population with a hereditary predisposition to multifocal pheochromocytoma. MATERIALS AND METHODS: All patients underwent a history, physical examination, serum and urine catecholamine determinations, abdominal computerized tomography-magnetic resonance imaging and metaiodobenzylguanidine scan. The adrenal gland was exposed using a standard 3 or 4 port approach. Intraoperative ultrasound was performed using a 7.5 MHz. 10 mm. transducer placed through a 12 mm. port. After imaging the whole gland and adjacent structures partial adrenalectomy was performed based on intraoperative ultrasound images using a harmonic scalpel or alternatively using a cut and sew technique that provided a 5 mm. margin. Tumors were removed intact and sent for pathological examination. RESULTS: Since 1998, 11 patients have undergone laparoscopic partial adrenalectomy. Intraoperative ultrasound was performed in 7 patients with suspected multiple adrenal masses, including 4 and 3 who underwent unilateral and bilateral laparoscopic partial nephrectomy, respectively. Six of the 7 patients had germline defects in the von Hippel-Lindau disease gene and 1 had no identifiable alteration in the von Hippel-Lindau disease or RET gene. A solitary tumor was identified in 3 cases and multiple lesions were noted in 4. In 1 case intraoperative ultrasound localized a tumor not identified on preoperative imaging that was not readily visible via laparoscopy. Intraoperative ultrasound guided surgical dissection in all cases and identified an extra-adrenal mass in 1 patient with bilateral adrenal masses. There were no complications due to intraoperative ultrasound and no conversions to open surgery. Mean operative time was 335 minutes and mean estimated blood loss was 179 ml. Histological study demonstrated pheochromocytoma in 14 lesions and the extra-adrenal mass proved to be a splenic rest. At short-term followup no recurrences have been noted. All patients retained sufficient adrenal cortical function to avoid steroid replacement therapy. CONCLUSIONS: Laparoscopic ultrasound differentiates normal adrenal parenchyma from adrenal tumors and facilitates laparoscopic partial adrenalectomy.

5
UI - 12028433
AU - Parfrey PS; Davidson WS; Green JS
TI - Clinical and genetic epidemiology of inherited renal disease in Newfoundland.
SO - Kidney Int 2002 Jun;61(6):1925-34
AD - Department of Medicine and Biochemistry, Memorial University, St. John's, Newfoundland, Canada. pparfrey@mun.ca
Clinical and genetic epidemiology of inherited renal disease in Newfoundland. Newfoundland's geography, settlement, and socioeconomic development have produced a population useful for the study of genetic diseases. This review examines the clinical and genetic epidemiologic studies of inherited renal diseases undertaken in this population in the past 15 years. Common founder effects and large families through each generation provided very extensive pedigrees with autosomal-dominant diseases, such as polycystic kidney disease (PKD) and von Hippel-Lindau disease. In the former disease the diagnostic utility of renal ultrasound was determined, as was the prognostic impact of genotype, the role of the renin-angiotensin system in the pre-hypertensive phase, the potential for somatic mutations of the PKD2 gene, or the combination of mutations in the PKD1 and PKD2 genes, in single cells to induce cysts, and the demonstration that human transheterozygotes of PKD1 and -2 are not embryonically lethal. The presence of multiple genetic isolates and the high coefficient of kinship have predisposed to autosomal recessive diseases such as Bardet-Biedl syndrome (BBS), autosomal-recessive PKD, primary hyperoxaluria, and dihydroxyadenine urolithiasis. We have reported the clinical manifestations and natural history of the BBS, with particular emphasis on the fact that renal abnormalities are cardinal manifestations of the disease, the presence of at least six different genotypes, the identity and function of the BBS6 gene, and the presence of three different BBS6 mutations. Because of its relatively homogenous origins and high coefficient of kinship, Newfoundland's population also may be useful for the study of complex diseases such as preeclampsia. Using unbiased ascertainment and strict diagnostic criteria, we have found a significant risk of preeclampsia and non-proteinuric gestational hypertension in sisters of probands with preeclampsia, particularly when probands are defined by severity of preeclampsia, an observation that supports a study to search for susceptibility genes. We conclude that collaborations between clinical epidemiologists and molecular geneticists, using the Newfoundland population, have provided important clinical and mechanistic insights into inherited renal diseases.

6
UI - 8791518
AU - Engelkamp D; van Heyningen V
TI - Transcription factors in disease.
SO - Curr Opin Genet Dev 1996 Jun;6(3):334-42
AD - MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK. dieter@hgu.mrc.ac.uk
Mutations affecting several predominantly tissue-specific transcriptional regulators have recently been associated with disease phenotypes. Although the mutational spectrum is variable, many of the reported cases involve clear loss-of-function mutations-such as Waardenburg syndrome type 1, aniridia and Rubinstein-Taybi syndrome-suggesting that the genetic mechanism involved in disease is haplo-insufficiency. The high degree of dosage sensitivity often appears to affect only a subset of the tissues that express the gene. Position effects with cytogenetic rearrangements well outside the coding region have been implicated for four of the genes discussed: POU3F4, SOX9, PAX6, and GL13.

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