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Mosaicism in von Hippel-Lindau disease: an event important to recognize.

Santarpia L, Sarlis NJ, Santarpia M, Sherman SI, Trimarchi F, Benvenga S - J. Cell. Mol. Med. (2007 Nov-Dec)

Bottom Line: The mosaic subject was found to have a cyst of the kidney and an angioma of the glans penis and had had surgery for a mandibular cyst and epididymal cystadenomas.Our results strongly suggest a complete and extensive clinical examination in the parents of each patient affected by an apparently de novo VHL germline mutation.We recommend performing a mutation screening of both parents of a proband with techniques that permit detection of low percentages of mosaicism before concluding that the proband has a de novo VHL mutation.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA.

ABSTRACT
von Hippel-Lindau disease (VHL) is an autosomal dominant, familial neoplastic disorder with variable interfamilial and intrafamilial expression. VHL is characterized by pre-disposition to development of a combination of benign and malignant tumours affecting multiple organs. We provide molecular evidence of somatic mosaicism in nearly asymptomatic man whose daughter had VHL. The mosaic subject was found to have a cyst of the kidney and an angioma of the glans penis and had had surgery for a mandibular cyst and epididymal cystadenomas. Mosaicism could provide a genetic explanation for the clinical heterogeneity and variable severity of VHL. The real incidence of mosaicism is still unclear and the identification of mosaicism has important consequences in genetic counseling of VHL patients who appear to have de novo VHL mutations and should be considered when evaluating patients with isolated VHL-related tumours. Our results strongly suggest a complete and extensive clinical examination in the parents of each patient affected by an apparently de novo VHL germline mutation. We recommend performing a mutation screening of both parents of a proband with techniques that permit detection of low percentages of mosaicism before concluding that the proband has a de novo VHL mutation.

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Sequencing analysis of exon 3 of the VHL gene in DNA from PBLs of the pro-band (A) and her father (B).
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fig03: Sequencing analysis of exon 3 of the VHL gene in DNA from PBLs of the pro-band (A) and her father (B).

Mentions: Sequence analysis demonstrated that the abnormal elution profile (abnormal peak) seen in the proband and at various levels in the different cells from the pro-band's father was the result of a missense mutation in exon 3. This mutation was a G-to-A substitution at cDNA nucleotide 695, predicting the replacement of wild-type arginine with glutamine codon 161 of pVHL (R161Q). The mutation-related peak in the PBLs DNA of the father was smaller than the same peak in the daughter's PBLs DNA (compare Fig. 3A with Fig. 3B), consistent with the fatherdaughter difference shown by DHPLC. Amplicon cloning revealed that only a few clones contained the G-to-A mutant allele. Of the 40 colonies studied, only six showed sequence mutations in semiquantitative analysis. Therefore, approximately 15% of father's PBLs harboured the mutation. In other words, in the DNA extracted from the father's circulating PBLs, the ratio of wild-type to mutated gene was approximately 85:15, instead of the 50:50 ratio expected in the absence of mosaicism.


Mosaicism in von Hippel-Lindau disease: an event important to recognize.

Santarpia L, Sarlis NJ, Santarpia M, Sherman SI, Trimarchi F, Benvenga S - J. Cell. Mol. Med. (2007 Nov-Dec)

Sequencing analysis of exon 3 of the VHL gene in DNA from PBLs of the pro-band (A) and her father (B).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401302&req=5

fig03: Sequencing analysis of exon 3 of the VHL gene in DNA from PBLs of the pro-band (A) and her father (B).
Mentions: Sequence analysis demonstrated that the abnormal elution profile (abnormal peak) seen in the proband and at various levels in the different cells from the pro-band's father was the result of a missense mutation in exon 3. This mutation was a G-to-A substitution at cDNA nucleotide 695, predicting the replacement of wild-type arginine with glutamine codon 161 of pVHL (R161Q). The mutation-related peak in the PBLs DNA of the father was smaller than the same peak in the daughter's PBLs DNA (compare Fig. 3A with Fig. 3B), consistent with the fatherdaughter difference shown by DHPLC. Amplicon cloning revealed that only a few clones contained the G-to-A mutant allele. Of the 40 colonies studied, only six showed sequence mutations in semiquantitative analysis. Therefore, approximately 15% of father's PBLs harboured the mutation. In other words, in the DNA extracted from the father's circulating PBLs, the ratio of wild-type to mutated gene was approximately 85:15, instead of the 50:50 ratio expected in the absence of mosaicism.

Bottom Line: The mosaic subject was found to have a cyst of the kidney and an angioma of the glans penis and had had surgery for a mandibular cyst and epididymal cystadenomas.Our results strongly suggest a complete and extensive clinical examination in the parents of each patient affected by an apparently de novo VHL germline mutation.We recommend performing a mutation screening of both parents of a proband with techniques that permit detection of low percentages of mosaicism before concluding that the proband has a de novo VHL mutation.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA.

ABSTRACT
von Hippel-Lindau disease (VHL) is an autosomal dominant, familial neoplastic disorder with variable interfamilial and intrafamilial expression. VHL is characterized by pre-disposition to development of a combination of benign and malignant tumours affecting multiple organs. We provide molecular evidence of somatic mosaicism in nearly asymptomatic man whose daughter had VHL. The mosaic subject was found to have a cyst of the kidney and an angioma of the glans penis and had had surgery for a mandibular cyst and epididymal cystadenomas. Mosaicism could provide a genetic explanation for the clinical heterogeneity and variable severity of VHL. The real incidence of mosaicism is still unclear and the identification of mosaicism has important consequences in genetic counseling of VHL patients who appear to have de novo VHL mutations and should be considered when evaluating patients with isolated VHL-related tumours. Our results strongly suggest a complete and extensive clinical examination in the parents of each patient affected by an apparently de novo VHL germline mutation. We recommend performing a mutation screening of both parents of a proband with techniques that permit detection of low percentages of mosaicism before concluding that the proband has a de novo VHL mutation.

Show MeSH
Related in: MedlinePlus