Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect

Hereditary paraganglioma type 1 (PGL1) is characterized by slow-growing and vascularized tumors that often develop in the carotid body (CB) and is caused by mutations in the gene for succinate dehydrogenase D ( SDHD) of mitochondrial complex II. The mechanisms of tumorigenesis and the factors affect...

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Bibliographic Details
Published in:Human genetics 2003-08, Vol.113 (3), p.228-237
Main Authors: ASTROM, Kristin, COHEN, Joel E, WILLETT-BROZICK, Joan E, ASTON, Christopher E, BAYSAL, Bora E
Format: Article
Language:English
Subjects:
Adrenal Gland Neoplasms - genetics
Altitude
Associated diseases and complications
Biological and medical sciences
Carotid Body Tumor - genetics
Diabetes. Impaired glucose tolerance
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Genetic Variation
Genetics, Population
Hereditary paraganglioma
Humans
Medical colleges
Medical sciences
Netherlands
Neurology
Oxygen - metabolism
Paraganglioma, Extra-Adrenal - enzymology
Paraganglioma, Extra-Adrenal - genetics
Phenotype
Pheochromocytoma - genetics
SDHD gene
Succinate Dehydrogenase - genetics
Tumors of the nervous system. Phacomatoses
United States
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Summary:Hereditary paraganglioma type 1 (PGL1) is characterized by slow-growing and vascularized tumors that often develop in the carotid body (CB) and is caused by mutations in the gene for succinate dehydrogenase D ( SDHD) of mitochondrial complex II. The mechanisms of tumorigenesis and the factors affecting penetrance and expressivity are unknown. Because chronic hypoxic stimulation at high altitudes causes sporadic CB paragangliomas, it has been hypothesized that the SDHD gene product may be involved in oxygen sensing. On this background, we examined genotype-phenotype-environment relationships and tested whether higher altitudes adversely affect the phenotype in PGL1. An analysis of 58 subjects from 23 families revealed that nonsense/splicing mutation carriers developed symptoms 8.5 years earlier than missense mutation carriers ( P
ISSN:0340-6717
1432-1203
DOI:10.1007/s00439-003-0969-6