A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23-qter

Abstract

Paragangliomas of the head and neck are slow growing tumors which rarely show malignant progression. Familial transmission has been described consistent with an autosomal dominant mode of inheritance. Clinical manifestations of hereditary paragangliomas are determined by the sex of the transmitting parent. All affected individuals have inherited the disease gene from their father, expression of the phenotype is not observed in the offspring of an affected female until subsequent transmittance of the gene through a male carrier. This finding strongly suggests that genomic imprinting is involved. We report the results of a linkage study on a large Dutch pedigree with hereditary paragangliomas. Highly significant evidence for genetic linkage to chromosome 11q23-qter with the anonymous DNA marker D11S147 was detected with a peak lod score of 6.0 at a recombination fraction theta = 0.0. Likelihood calculations yielded an odds ratio of 2.7 x 10(6) in favor of genomic imprinting versus the absence of genomic imprinting.

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

“…So far, no mutations have been detected. Previously, linkage calculations have provided evi dence for genomic imprinting of the distally located gene (Heutink et al 1992). The same gene probably underlies the disorder in our present Family 2, where the pattern of inheritance is consistent with genomic imprinting.…”

“…3) was performed with D11S956 and PYGM, which are separated by 5cM (Litt et al 1993), and with D11S897 and D11S490 at a distance of 14cM (C11M19, Cl 1M48 of GDB). Ge nomic imprinting was assumed for the second and third generation, and was incorporated into the linkage calculations by a separate lia bility class with a penetrance of 0 .0 for children of female gene car riers (Heutink et al 1992). For most marker loci, linkage analyses were based on the reported allele frequencies, except for CNTF and D11S480.…”

Germline SDHD mutation in paraganglioma of the spinal cord

“…The most common locus is in the chromosomal region 11q22.3-q23, and another locus is in the 11q13.1 region (Heutink et al, 1992(Heutink et al, , 1994Mariman et al, 1995). The SDHD gene located at 11q23 was recently shown to be mutated in the germline of families with hereditary paragangliomas (Baysal et al, 2000).…”

Jugulotympanic paragangliomas: 75 years of evolution in understanding

“…The first loci responsible for familial glomus tumors, PGL1 and PGL2, were identified on chromosome 11 in 1992 and 1995, respectively. 21,34 The next loci, PGL3 and PGL4, were identified 7 years later on chromosome 1. 4,40,41 Because 3 of the mutated gene products of the PGL loci are subunits of SDHD, these mutations have now been renamed as SDHD (PGL1), SDHC (PGL3), and SDHB (PGL4) to more accurately reflect the protein subunit with the mutation.…”