mmary of Work: The goal of this work is to understand the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those that are hereditary and associated with multiple tumors and abnormalities in other endocrine glands (i.e. the pituitary gland) and tissues of neuroectodermal origin (i.e. the melanocytes). Our laboratory has studied families with Carney complex (CC) (also known as the icomplex of myxomas, spotty skin pigmentation, endocrine overactivity and schwannomasi) and related syndromes. Through genetic linkage analysis two genomic loci harboring genes for CC have been identified on human chromosomes 2 and 17 (corresponding to cytogenetic bands 2p15-16 and 17q21-22, respectively). A comprehensive genetic and physical map of the 2p16 chromosomal region is currently under construction for the cloning of CC-causing gene(s), through meiotic and radiation hybrid analysis of sequence tagged sites (STS) cloned from this genomic area and the synthesis of yeast and bacterial artificial chromosomes (YAC/BAC) contig that cover 10 Mb on 2p15-16. Through studies in cultured primary tumor cell lines established from our patients a region of amplification has been identified in the center of this contig; 4 novel genes (with unknown function) have been identified and are currently being screened for mutations in patients with CC and other disorders mapped in the area. In collaboration with Mayo Clinic, the genetic defects in patients with CC-related syndromes (i.e. Peutz-Jeghers syndrome) are being identified. Genome wide screens are also ongoing in our laboratory for the identification of childhood adrenocortical cancer-related genes and the gene(s) responsible for inherited adrenocortical aldosteronomas (familial hyperaldosteronism type-II).""""""""
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