Thus chronic hypoxic stimulation was the common underlying factor leading to carotid body enlargement. Chronic hypoxic stimulation has also been implicated in the development other head and neck paragangliomas, such as glomus jugulare tumors. The physiological role of the carotid body in oxygen sensing and the recurrent observations linking paraganglioma tumor development to chronic hypoxic stress gave us some clues in interpreting the genetic basis of PGL tumors. The phenotypic features of PGL tumors, including their benign biological behavior, limited organ involvement, and microscopic structure, were markedly similar to those developed when normal CBs were challenged by chronic hypoxic stimulation. This line of reasoning led us to select a gene encoding a protein transported to mitochondria.
Mitochondria are the power plants of the cell that use oxygen to create energy.
The SDHD gene was previously mapped to 11q23. We tested the PGL families who showed linkage to the PGL1 locus at 11q23, for germ line SDHD mutations. We found a variety of SDHD mutations segregating with the disease-carrying chromosomes. These mutations included those replacing conserved amino acids and causing premature termination of protein production. Thus, these mutations were very likely to result in loss of function of the protein product, cybS. The mutations co-segregated perfectly with the disease phenotype in all affected individuals in the PGL families.