Fine mapping of a putatively imprinted gene for familial non-chromaffin paragangliomas to chromosome 11q13.1: evidence for genetic heterogeneity

Abstract

A bstract Autosomal, dominantly inherited, non-chro maffin paragangliomas are tumors of the head and neck region occurring with a frequency of 1:30 000. Genomic imprinting probably influences the expression of the dis order, because tumor development is limited to individu als who have inherited the trait from their father. By link age analysis and haplotyping of a single large family in which the pattern of inheritance is consistent with ge nomic imprinting, we have mapped the gene to a 5 cM re gion of chromosome 1 lq 13.1 between D11S956 and PYGM. A maximum lod score of 7.62 at © = 0.0 was ob tained for D11S480. This interval does not overlap with a recently assigned locus for glomus tumors in other fami lies; 1 Iq22.3-q23.3. Furthermore, analysis of a second family showing the imprinting phenomenon resulted in the exclusion of the 5 cM area as the location of the dis ease gene, whereas an indication for linkage was obtained (Z = +2.65) with markers from the distal locus. These ob servations argue for the presence of two distinct imprinted genes for glomus tumors on 1 lq. A model for tumor initi ation and progression is presented based on all available information.

The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family

“…13,14 Recently, new insights in the mechanisms behind this peculiar inheritance pattern have emerged. We have shown previously that in SDHD-linked paragangliomas, not only the wild-type maternal SDHD allele on 11q23 but the entire maternal copy of chromosome 11 was consistently lost.…”

“…6,12 As a rule, individuals are at risk only when they inherit the mutant SDHD allele from the father (regardless of his clinical status) and not when the mutation is maternally inherited. 13,14 Thus, proper genetic counseling of SDHD-linked paraganglioma families requires knowledge about the risk of developing head and neck paraganglioma upon paternal transmission of a SDHD mutation (penetrance), the risk of developing clinical symptoms, the age at onset of the disease, the risk of developing multiple tumors and the risk of developing phaeochromocytoma. To date, two reports have discussed the risk of developing paraganglioma or phaeochromocytoma upon inheritance of a SDHD mutation.…”

A complete Not I restriction map covering the entire long arm of human chromosome 11

“…The long arm of human chromosome 11 contains pathologically important regions. Several uncloned disease loci have been mapped which include vitelliform macular dystrophy (Best's Disease, VMD2) at 11q13.1 (Graff et al 1994), hereditary paraganglioma 2 (PGL2) at 11q13.1 (Mariman et al 1995), multiple endocrine neoplasia, type 1 (MEN 1) at 11q13.1 (Fujimori et al 1992;Courseaux et al 1996), spinocerebellar ataxia, type 5 (SCA5) at 11q13.1 (Ranum et al 1994), insulin-dependent diabetes mellitus 4 (IDDM4) at 11q13 (Davies et al 1994;Hashimoto et al 1994), osteoporosis-pseudoglioma syndrome (OPS) at 11q12-q13 (Gong et al 1996), exudative vitreoretinopathy 1 (EVR1) at 11q13-q21 (Li et al 1992), neovascular inflammatory vitreoretinopathy (VRN1) at 11q13.1 (Stone et al 1992), and hereditary paraganglioma 1 (PGL1) at 11q23.1 (Devilee et al 1994). In addition, the long arm of human chromosome 11 has repeatedly been found to be deleted in neoplasia.…”

Maternal-Specific Methylation of the HumanIGF2RGene Is Not Accompanied by Allele-Specific Transcription

“…de. 1992Feinberg, 1993;Mariman et aL, 1995). At pres ent, the nature of the primary im print and the molecu lar basis by which genes are recognized as paternally or maternally derived are still unknown.…”