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

Abstract

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.

von Hippel–Lindau disease: A clinical and scientific review

“…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. 45 The remaining mutations fall into two groups, missense substitutions and mutations predicted to cause truncated protein (nonsense, indels, splice site). In non-mosaic patients with classical VHL disease mutation detection is 495%.…”

“…However a subgroup of patients with a contiguous deletion of all or part of VHL and the HSPC300 gene develop retinal and CNS haemangioblastomas but have a low risk of RCC (sometimes called Type 1B phenotype). [45][46][47] Kindreds with phaeochromocytoma are designated as Type 2 VHL disease and usually have a germline missense mutation. Most such families are further characterised as Type 2B and manifest haemangioblastomas, RCC and phaeochromocytoma but Type 2A families manifest haemangioblastomas and phaeochromocytoma with a lower risk of RCC.…”

Genetic analysis of von Hippel-Lindau disease

“…Some have found that VHL deletions extending to include the actin-regulator gene HSPC300 appear to lower the risk of RCC and retinal angiomas development [Franke et al, 2009;Maranchie et al, 2004]. Nonsense and frameshift mutations have a higher age-related risk for RCC and hemangioblastomas than missense mutations thought to interfere with pVHL's structural integrity [Ong et al, 2007].…”

Nuclear function ofAlus

“…53 Alu mediated recombination is one of the major cause for genome instability and chromosome translocation, underlining various diseases 54,55 and malignancy. [56][57][58] Closely related to recombination, Alus are (as with other TEs) sites prone to DNA damage. Alus are recently found enriched in chromosome common fragile sites, 59 which tend to break, although they are part of normal chromosome structure and play an important function in sister chromatid exchange and other recombinatory functions.…”