Oculodentodigital dysplasia (ODDD) is a syndrome with an autosomal dominant pattern of inheritance. The phenotype includes dental, craniofacial, ocular, hand, foot, and long bone abnormalities. Central nervous system signs and symptoms related to white matter degeneration can occur in some ODDD patients. These neurological manifestations and some dysmorphic features may be more severe or occur at an earlier age in successive generations of ODDD kindreds, suggestive of a phenomenon known as """"""""genetic anticipation."""""""" The Principal Investigator has confirmed linkage of this condition to chromosome 6 and narrowed the candidate region to a 1.01 to 2.87 cM region between DNA markers D6S266 and D6S1639. This candidate region physically maps within two overlapping YAC clones. The overall goal of this project is to identify the gene associated with ODDD.
The specific aims of the proposal are to 1.) Ascertain additional ODDD families and sporadic cases, refine the ODDD genetic map location by linkage and haplotype analyses, and refine the ODDD physical map location by constructing YAC, PAC, BAC, and cosmid contigs; 2.) Isolate candidate cDNAs in the critical region; 3.) Identify the disease gene by detecting mutations; and 4.) Perform phenotype/genotype correlations. Isolations of the gene will be important for accurate diagnosis and identification of genetic factors involved in dental, craniofacial, ocular, limb, bone, and brain development. Knowledge of the ODDD gene increases our understanding of the normal process of craniofacial development, as well as of other development pathways.
|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|