Oculodentodigital dysplasia (ODDD) is a syndrome with an autosomal dominant pattern of inheritance, high penetrance, and variable expressivity. The phenotype includes dental, craniofacial, ocular, hand, and foot abnormalities. Central nervous system signs and symptoms related to white matter degeneration, palmar and plantar keratoderma, and cardiac abnormalities occur in some ODDD patients. Our laboratory recently identified mutations (missense and small duplication) in the gap junction protein GJA1, also referred to as connexin 43, in ODDD patients. This connexin and other connexin proteins are known to form connexons that align as pairs in apposing cell membranes to form specialized intercellular gap junctions. These channels confer distinct physiologic properties by providing an intercellular passage for ions and small molecules. Identification of this disease gene now allows us to study the pathophysiology of ODDD at the molecular level. The goal of this application is to investigate the functional changes in the mutant protein and correlate these effects to the phenotypic features observed in this condition. The following hypotheses will be tested: 1) The GJA1 mutations found in ODDD patients alter the function of the mutant allele and causes aberrant gap junction channels to form. These aberrant connexons lead to lack of gap junction formation or to gap junctions that are functionally altered. 2) GJA1 mutations alter gap junction intercellular communication of calcium signaling via mutant connexin 43 hemichannels. 3) The phenotypic pleiotropy observed in ODDD are due to interactions among the mutant connexin 43 and other members of the connexin protein family that alter expression or heterotypic pairings of connexons in affected tissues. Cellular transfection studies, utilizing mammalian cells and Xenopus oocytes, and creation of mutant GJA1 transgenic mice with alterations analogous to the mutations found in patients will serve as model systems to study embryonic and pathophysiologic aspects of ODDD. The information generated by these developmental and functional studies will increase our understanding of the normal process of craniofacial and dental development, as well as of other abnormal processes including postnatal neurodegeneration.
