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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
Project #
Application #
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Scholnick, Steven
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mount Sinai School of Medicine
Schools of Medicine
New York
United States
Zip Code
Chassaing, N; Ragge, N; Kariminejad, A et al. (2013) Mutation analysis of the STRA6 gene in isolated and non-isolated anophthalmia/microphthalmia. Clin Genet 83:244-50
Chassaing, Nicolas; Sorrentino, Susanna; Davis, Erica E et al. (2012) OTX2 mutations contribute to the otocephaly-dysgnathia complex. J Med Genet 49:373-9
Paznekas, William A; Karczeski, Barbara; Vermeer, Sascha et al. (2009) GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype. Hum Mutat 30:724-33
Chtchetinin, Jana; Gifford, Wes D; Li, Sichen et al. (2009) Tyrosine-dependent basolateral targeting of human connexin43-eYFP in Madin-Darby canine kidney cells can be disrupted by the oculodentodigital dysplasia mutation L90V. FEBS J 276:6992-7005
Lai, Albert; Le, Dung-Nghi; Paznekas, William A et al. (2006) Oculodentodigital dysplasia connexin43 mutations result in non-functional connexin hemichannels and gap junctions in C6 glioma cells. J Cell Sci 119:532-41
Shibayama, Junko; Paznekas, William; Seki, Akiko et al. (2005) Functional characterization of connexin43 mutations found in patients with oculodentodigital dysplasia. Circ Res 96:e83-91
Seki, Akiko; Coombs, Wanda; Taffet, Steven M et al. (2004) Loss of electrical communication, but not plaque formation, after mutations in the cytoplasmic loop of connexin43. Heart Rhythm 1:227-33
Paznekas, William A; Boyadjiev, Simeon A; Shapiro, Robert E et al. (2003) Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet 72:408-18
Boyadjiev, S A; Chowdry, A B; Shapiro, R E et al. (2002) Physical map of the chromosome 6q22 region containing the oculodentodigital dysplasia locus: analysis of thirteen candidate genes and identification of novel ESTs and DNA polymorphisms. Cytogenet Genome Res 98:29-37