Molecular Characterization of Large Deletions in the von Hippel-Lindau (VHL) Gene by Quantitative Real-Time PCR

Casarin, Alberto; Martella, Maddalena; Polli, Roberta; Leonardi, Emanuela; Anesi, Laura; Murgia, Alessandra

doi:10.1007/bf03256463

Cited by 24 publications

(25 citation statements)

References 24 publications

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“…The two different large gene deletions detected in two VHL probands with type 1 disease may also exert a severe impact on protein function. Large gene deletions, which occurred in about 20% of patients with VHL disease in previous studies (32), usually cause VHL type 1, but there are recent reports on Belgian and Polish 'CNS hemangioblastoma only' families (30,33).…”

Section: Discussionmentioning

confidence: 99%

Germline VHL gene mutations in Hungarian families with von Hippel–Lindau disease and patients with apparently sporadic unilateral pheochromocytomas

Gergics

Patócs

Tóth

et al. 2009

European Journal of Endocrinology

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Objective: Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome caused by mutations or deletions of the VHL tumor-suppressor gene. Germline VHL gene alterations may be also present in patients with apparently sporadic pheochromocytoma (ASP), although a wide variation in mutation frequencies has been reported in different patient cohorts. Design: Herein, we report the analysis of the VHL gene in Hungarian families with VHL disease and in those with ASP. Methods: Seven families (35 members) with VHL disease and 37 unrelated patients with unilateral ASP were analyzed. Patients were clinically evaluated and the VHL gene was analyzed using direct sequencing, multiplex ligation-dependent probe amplification, and real-time PCR with SYBR Green chemistry. Results: Disease-causing genetic abnormalities were identified in each of the seven VHL families and in 3 out of the 37 patients with ASP (one nonsense and six missense mutations, two large gene deletions and one novel 2 bp deletion). Large gene deletions and other genetic alterations resulting in truncated VHL protein were found only in families with VHL type 1, whereas missense mutations were associated mainly, although not exclusively, with VHL type 2B and type 2C. Conclusions: The spectrum of VHL gene abnormalities in the Hungarian population is similar to that observed in Western, Japanese, or Chinese VHL kindreds. The presence of VHL gene mutations in 3 out of the 37 patients with ASP suggests that genetic testing is useful not only in patients with VHL disease but also in those with ASP.

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Section: Discussionmentioning

confidence: 99%

Germline VHL gene mutations in Hungarian families with von Hippel–Lindau disease and patients with apparently sporadic unilateral pheochromocytomas

Gergics

Patócs

Tóth

et al. 2009

European Journal of Endocrinology

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“…Indeed, there are numerous reports of disease-causing deletions resulting from recombination between Alu elements (Batzer and Deininger, 2002;Nishimura et al, 2005;Casarin et al, 2006;Has et al, 2006;Kozak et al, 2006;Li et al, 2006;Matejas et al, 2006;Nissen et al, 2006;Sen et al, 2006;Shabbeer et al, 2006;Uddin et al, 2006;Xie et al, 2006;Zhang et al, 2006). If a large proportion of Alu elements indeed fosters euchromatic domains as suggested by the aforementioned study (Willoughby et al, 2000), then flanking sequences may also be destabilized.…”

Section: Non-random Repeat Distributions Via Natural Selectionmentioning

confidence: 94%

Repetitive sequence environment distinguishes housekeeping genes

Eller¹,

Regelson²,

Merriman³

et al. 2007

Gene

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Housekeeping genes are expressed across a wide variety of tissues. Since repetitive sequences have been reported to influence the expression of individual genes, we employed a novel approach to determine whether housekeeping genes can be distinguished from tissue-specific genes their repetitive sequence context. We show that Alu elements are more highly concentrated around housekeeping genes while various longer (>400-bp) repetitive sequences ("repeats"), including Long Interspersed Nuclear Element 1 (LINE-1) elements, are excluded from these regions. We further show that isochore membership does not distinguish housekeeping genes from tissue-specific genes and that repetitive sequence environment distinguishes housekeeping genes from tissue-specific genes in every isochore. The distinct repetitive sequence environment, in combination with other previously published sequence properties of housekeeping genes, were used to develop a method of predicting housekeeping genes on the basis of DNA sequence alone. Using expression across tissue types as a measure of success, we demonstrate that repetitive sequence environment is by far the most important sequence feature identified to date for distinguishing housekeeping genes.

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“…In two previous VHL deletion studies, a reduced risk for renal cell carcinoma has been noted when the actin regulator gene HSPC300 was codeleted together with the VHL gene [Maranchie et al, 2004;Cascó n et al, 2007]. While a number of studies have characterized partial and complete germline deletions of the VHL gene by quantitative Southern blot, multiplex ligation-dependent probe amplification (MLPA), and/or quantitative real-time polymerase chain analyses (qPCR) [Stolle et al, 1998;Hes et al, 2000;Cybulski et al, 2002;Gallou et al, 2004;Maranchie et al, 2004;Hoebeeck et al, 2005;Casarin et al, 2006;Hattori et al, 2006;Cascó n et al, 2007;Hes et al, 2007;Huang et al, 2007;Ong et al, 2007] and while some of the breakpoints have been narrowed down more precisely, the exact breakpoint sequence has only been determined for one case, which was shown to result from Alu-Alu recombination [Casarin et al, 2006]. Alu-Alu recombination-mediated deletions have been described for various inherited disorders such as familial hypercholesterolemia and a-thalassemia [for reviews see Deininger and Batzer, 1999;Batzer and Deininger, 2002].…”

Section: Official Journal Wwwhgvsorgmentioning

confidence: 99%

Alu-Alurecombination underlies the vast majority of largeVHLgermline deletions: Molecular characterization and genotype-phenotype correlations in VHL patients

et al. 2009

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Von Hippel-Lindau disease (VHL) is an autosomal dominant cancer syndrome. Affected individuals are predisposed to multiple tumors, primarily of the central nervous system (CNS), eyes, adrenals, and kidneys. The VHL tumor suppressor gene on chromosome 3p26-25 is partially or completely deleted in 20 to 30% of families with VHL. We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families. In 33 of the index patients, the breakpoints were precisely characterized by DNA sequencing. Of the 66 breakpoints, 90% were located in Alu elements, revealing Alu-mediated recombination as the major mechanism for large germline deletions of the VHL gene, which lies in a region of high Alu density. Interestingly, an AluYa5 element in VHL intron 2, the evolutionarily youngest Alu element and the only such element in the entire region, was found to be the most recombinogenic, involved in 7 out of the 33 deletions. In comparison to VHL patients in general, the 54 index cases and their affected relatives showed a higher occurrence of renal cell carcinomas (RCC) and of CNS hemangioblastomas. We not only noted the association of RCC with retention of the HSPC300 gene, but also observed a significant correlation between retention of HSPC300 and the development of retinal angiomas (AR). This study reveals that germline VHL deletions provide a particularly rich source for the study of Alu-mediated unequal crossover events, and provides evidence for a protective role of the loss of the actin-regulator gene HSPC300 for the development of both RCC and AR.

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Molecular Characterization of Large Deletions in the von Hippel-Lindau (VHL) Gene by Quantitative Real-Time PCR

Cited by 24 publications

References 24 publications

Germline VHL gene mutations in Hungarian families with von Hippel–Lindau disease and patients with apparently sporadic unilateral pheochromocytomas

Germline VHL gene mutations in Hungarian families with von Hippel–Lindau disease and patients with apparently sporadic unilateral pheochromocytomas

Repetitive sequence environment distinguishes housekeeping genes

Alu-Alurecombination underlies the vast majority of largeVHLgermline deletions: Molecular characterization and genotype-phenotype correlations in VHL patients

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