In this study we propose to identify and characterize two genes that cause isolated hereditary gingival fibromatosis (HGF). Gingival fibromatosis refers to a clinical condition that involves enlargement of the keratinized gingiva surrounding the teeth. The condition may occur as a simple Mendelian trait, as part of a genetic syndrome, or following exposure to certain pharmacological agents. The genes responsible for hereditary gingival fibromatosis are unknown, and the underlying etiology is not understood. Attempts to elucidate the etiology of hereditary gingival fibromatosis are limited by genetic heterogeneity, diagnostic difficulties and a lack of unifying scientific hypotheses. Identification of the genetic basis for HGF will increase our understanding of the growth and development of gingival tissues and permit identification of homogeneous study populations. We will employ gene mapping strategies to identify two genes for HGF. We have identified two large families segregating a highly penetrant, autosomal dominant form of HGF. We have localized an HGF gene to chromosome 2p2l in one family (Family number 1), and have excluded an HGF gene from this region in a second family (Family number 2), demonstrating genetic heterogeneity. We propose to continue genetic linkage studies to sublocalize the HGF gene on chromosome 2p21, and also to identify the chromosomal location for the HGF gene in Family number 2. Molecular and cytogenetic studies will be performed to resolve physical and genetic maps of the candidate regions, and to help identify candidate genes/ESTs for the HGF loci. Strategies for gene identification and mutational analysis will be utilized to evaluate and identify genes and the specific gene mutations responsible for HGF in these two families. Completion of these specific aims will for the first time, identify genes responsible for HGF. Identification of the molecular basis for HGF will provide valuable information to study the biologic basis of the condition. Understanding the genetic causes for HGF has implications for diagnosis and treatment of isolated HGF, as well as syndromic and pharmacologically induced forms of gingival fibromatosis.