Inherited mutations in genes encoding three of the four subunits of mitochondrial complex II cause familial predisposition to hereditary paraganglioma (PGL). PGL is characterized by the development of vascularized tumors, in the head and neck and abdomen, and derive from oxygen sensing cells. How mitochondrial defects could lead to tumor formation is a mystery, because mitochondria are primarily involved in energy production. Mutations in the smallest subunit of complex II, encoded by a gene named SDHD, are the primary cause of head and neck paragangliomas. Mutations in SDHD cause tumors when they are transmitted from a father to his children, but no tumor development is seen if the mutations are transmitted from a mother. This phenomenon is known as genomic imprinting. Genomic imprinting causes differences in the function of genes depending on its parental origin. The mechanism of imprinting in PGL is unknown. Understanding the mechanism of genomic imprinting in PGL is important because genomic imprinting determines whether a mutation carrier will suffer from multiple tumors or remain entirely tumor-free lifelong. Although there are other disorders that are influenced by genomic imprinting, PGL is unique because impact of genomic imprinting on a single mutated gene leads to either disease or to complete normalcy. This application primarily proposes to study molecular basis of genomic imprinting in PGL.
The specific aims i nclude determination of molecular signs of genomic imprinting such as gene expression and DNA methylation differences, which are commonly observed around other imprinted genes. These molecular signs often distinguish the maternal and paternal copies of an imprinted gene. We will also study another mechanism of gene control, called transcript editing, as another means of controlling the amount of mitochondrial complex II in the cell. Understanding the molecular basis of imprinting in PGL may provide general insights on how differential expression of a single defective gene can lead to disease or normalcy.
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