Abstract
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<0.012). We also found that subjects who were diagnosed with single tumors at their first clinical evaluation lived at lower average altitudes and were exposed to lower altitude-years than those with multiple tumors (P<0.012). Pheochromocytomas developed in six subjects (approximately 10%), five of whom had nonsense mutations (P=0.052). Subjects with pheochromocytomas also lived at higher average altitudes and were exposed to higher altitude-years than those without them (P=0.026). To test whether altitude is also associated with the more frequent detection of germ-line founder mutations among sporadic cases in The Netherlands than in the USA (P=0.00033), we calculated population-weighted elevations of the two countries. We found that the population-weighted elevations were approximately 260 m for the US and 2 m for the central-western Netherlands (P~0), where three Dutch founder mutations were discovered. This finding suggests that low altitudes in The Netherlands reduce penetrance and relax the natural selection on SDHD mutations. Collectively, these data suggest that higher altitudes and nonsense/splicing mutations are associated with phenotypic severity in PGL1 and support the hypothesis that SDHD mutations impair oxygen sensing.
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Acknowledgements
We thank all PGL1 subjects for their help; this study would not have been possible without their participation. We also thank Drs. E.N. Myers, E. Böke, E.C. Ridgway, R.A. Spritz for referring patients, Dr. R.E. Ferrell and Mrs. E.C. Lawrence for help in sequencing family PGL20, Dr. Myers for stipend support to K.A, and Dr. W.S. Rubinstein for helpful discussions. J.E.C. thanks the US NSF for grant DEB9981552 and Mr. and Mrs. W.T. Golden for hospitality during this work.
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Astrom, K., Cohen, J.E., Willett-Brozick, J.E. et al. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet 113, 228–237 (2003). https://doi.org/10.1007/s00439-003-0969-6
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DOI: https://doi.org/10.1007/s00439-003-0969-6