aglogo.gif (1177 bytes)Search for the gene-defect in a family with paragangliomas of the head and neck region

Background of research project:

Non-chromaffin paragangliomas, or glomus tumors, are benign and slow growing tumors of the extra-adrenal paraganglion system, usually occurring at the carotid bifurcation in the head and neck region. Their incidence in the population is low, but a substantial proportion of them are due to a genetic defect that has been mapped to the long arm of chromosome 11 (11q22-q23). The inheritance pattern, however, is non-Mendelian and strongly suggests that the gene, PGL1, is subject to genomic imprinting. Recently, PGL1 was unmasked as being the SDHD gene, a subunit of the mitochondrial cytochrome B complex II. Germline mutations in SDHD have been found in nearly all paraganglioma families, and in about a third of all non-familial (sporadic) cases. In one very large pedigree, however, no mutations have been detected, in agreement with earlier findings that the gene-defect causing the disease in this family (PGL2) maps to another region on chromosome 11.

Research questions:

To identify the PGL2 gene-defect by haplotyping and mutation analysis in candidate genes

Project description:

The second paraganglioma gene, PGL2, has been assigned to a 5-cM interval on 11q13. We will attempt to narrow this region further by more accurate definition of the haplotype shared among patients by typing new markers from the region. In addition, the human genome project has finished a first draft-sequence of this region, allowing an inventory of all genes and expressed sequences. We will select a few of these genes for mutation analysis on the basis of the role that SDHD is playing in the genesis of paragangliomas. It seems plausible that PGL2 causes paragangliomas in a similar biochemical way as SDHD.

Experimental design:

DNA from family members will be genotyped at polymorphic markers in the 5-cM candidate region and their haplotypes be reconstructed. This may lead to a refinement of the chromosomal region that harbours PGL2. We shall then examine the physical gene-map of this region by database-mining of genome databases. The presence of interesting genes on the map will be verified by PCR of YAC and BAC clones containing inserts from the region. The exon-intron organisation will be reconstructed by database-mining, sequence comparisons, and targeted PCRs. Exons will then be subjected to mutation analysis in at least three patients in three branches of the family.

Techniques to be applied:

Database mining (by internet searches of genome databases); software-assisted sequence alignments; handling Bac and YAC clones; PCR; mutation screening; DNA sequencing.

Statistical methods:


Plan of work and time schedule:

The first phase will entail the accurate haplotyping of the region. Meanwhile, computer-assisted analysis of the physical map of the region is performed. Once candidate genes are selected, their exon-intron structure will be worked out. The final phase concerns screening the exons for the presence of deleterious mutations in at least 3 paraganglioma patients from the PGL2-linked family.

Equipment to be used:

PCR Thermocycler; automated DNA sequencer

Patients involved

Yes, 3-5

Laboratory animals involved




Approval required from the Committee on medical ethics


Approval required from the committee on the use of laboratory animals


Updated:  19-02-2003
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