Genotype Phenotype Correlations in VHL

The phenotypic expression of VHL disease can vary widely between families, and specific correlations of genotype and phenotype are now recognized. Von Hippel-Lindau Type 1 families typically have deletions (46%), missense (44%), and nonsense (10%) mutations (reviewed in Ref. [17]) (Fig. 1A). These missense mutations are frequently observed in the p-domain of pVHL and are predicted to lead to loss of function of pVHL by disrupting the protein's hydrophobic core (Fig. 1B). In particular, mutations in exon 2 cause loss of the ability of pVHL to shuttle between the nucleus and the cytoplasm, leading to loss of regulation of hypoxia-inducible genes.[18]

In general, the majority of kindreds with VHL Type 2B disease and virtually all Type 2A and 2C patients have missense mutations.[5] In Types 2A and 2B, either binding to elongin C (a domain of VHL) or the HIF-a binding site (VHL p domain) is affected by mutations, thus interrupt-

Who should undergo genetic screening for VHL?

Presymptomatic, predictive mutation analysis is recommended for all at-risk members of a family with VHL, increasing the diagnostic power of the clinician. Given the direct benefit of early, appropriate clinical screening in this condition, knowledge of young mutation carriers and immediate instigation of a clinical management program may be integral to the prevention of malignant tumor development, loss of sight and hearing. As VHL is an autosomal dominant condition, the offspring of an affected parent have a 50% chance of inheriting a VHL mutation. If after predictive testing the at-risk family member is shown not to carry the VHL mutation present in the family, no additional genetic or clinical screening is required. A recent study of VHL patients' attitudes toward presymptomatic genetic diagnosis in children as well as prenatal genetic diagnosis reports a wide range of opinions, indicating that these areas remain controver-sial.[20]

It should be noted that approximately 50% of PHEO-only families with no other evidence of VHL disease may have germline VHL mutations. Other familial syndromes where PHEO may present as the sole phenotype include multiple endocrine neoplasia Type 2 (mutations in the RET protooncogene) and pheochromocytoma-paragan-glioma syndrome [mutations in the succinate dehydrogenase (SDH) genes SDHB, SDHC, and SDHD, encoding three of the four subunits of mitochondrial complex II] (reviewed in Ref. [21]). In addition, VHL germline mutations in 3-11% of patients with apparently sporadic PHEO have been reported.[22]

Standard molecular techniques used for VHL mutation scanning

The heterogeneity of mutation type seen in VHL means that multiple molecular techniques are required to enable a complete mutation scan. Mutations have been identified in nearly 100% of VHL families using a combination of fluorescence in situ hybridization (FISH), Southern blotting, and sequencing of the coding and flanking regions of VHL.[12]

dHPLC—Suitable for detecting a subset of VHL mutations

More recently, denaturing high-performance liquid chromatography (dHPLC) has been used as an alternative to sequence analysis for rapid scanning for mutations in VHL.[23,24] This technique makes use of mismatched heteroduplex formation due to the presence of a mutant and wild-type allele. Mismatched heteroduplexes, and mutant and wild-type homoduplexes, can be distinguished after elution from a chromatographic column at a predetermined temperature based on sequence-specific thermostabilities. Given that gross germline deletion of VHL and its flanking intervals have been reported in VHL (predominantly those with Type 1), it is important to recognize that standard dHPLC would not be a suitable screening tool for this subset as the presence of only one allele would preclude the formation of heteroduplexes.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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