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Title: A model for the initiation and progression of non-chromaffin paragangliomas: An autosomal dominant disorder with genetic heterogeneity and genomic imprinting

Non-chromaffin paragangliomas are autosomal dominantly inherited tumors of the head and neck region (frequency: 1:30,000). Genomic imprinting influences the expression of the disorder. Tumor development is restricted to offspring of male disease gene carriers. By linkage analysis and haplotyping of a single family, in which the pattern of inheritance is consistent with genomic imprinting, we have mapped the gene to a 5 cM region of chromosome 11q13.1 between D11S956 and PYGM. A maximum lod score of 7.62 at {theta}=0.0 was obtained for D11S480. This interval does not overlap with the segment 11q22.3-q23.3, to which a locus for glomus tumors has been assigned in other families. Moreover, the 5cM interval was excluded as the location of the disease gene in a second family showing the imprinting phenomenon, whereas an indication for linkage was obtained (Z=+2.65) with markers from the distal locus. These observations argue for the presence of two distinct imprinted genes for paragangliomas on 11q. Clinical findings suggest that at least one, but probably both genes code for tumor suppressor required for tumor initiation. According to this model, imprinting would account for the silencing of the two maternal copies, whereas a paternal copy would be inactive due to an inheritedmore » mutation. Tumors would then result from somatic inactivation of the other paternal gene copy in individual cells. In tumors, relaxation of imprinting seems to be a frequent feature. Here, it would necessitate subsequent inactivation of maternal gene copies to allow tumor progression. Indeed, selective loss of maternal alleles in paragangliomas has been observed with markers from 11 q. Definite proof for this model should come from the isolation and expression studies of the involved genes.« less
Authors:
; ;  [1]
  1. University Hospital Nijmegen (Netherlands) [and others
Publication Date:
OSTI Identifier:
133538
Report Number(s):
CONF-941009--
Journal ID: AJHGAG; ISSN 0002-9297; TRN: 95:005313-0266
Resource Type:
Journal Article
Resource Relation:
Journal Name: American Journal of Human Genetics; Journal Volume: 55; Journal Issue: Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; GENES; GENE MUTATIONS; HUMAN CHROMOSOMES; GENETIC MAPPING; CHROMOSOMAL ABERRATIONS; HEAD; NEOPLASMS; NECK; PATHOGENESIS; BIOLOGICAL MODELS; DOMINANT MUTATIONS; GENETICS; STATISTICS; BIOLOGICAL MARKERS; SOMATIC MUTATIONS