GENETIC STUDIES OF ODDD
Principal Investigator: ETHYLIN JABS
Abstract: 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.
Funding Period: ----------------2000 - ---------------2011-
more information: NIH RePORT
- Oculodentodigital dysplasia connexin43 mutations result in non-functional connexin hemichannels and gap junctions in C6 glioma cellsAlbert Lai
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
J Cell Sci 119:532-41. 2006....
- OTX2 mutations contribute to the otocephaly-dysgnathia complexNicolas Chassaing
Department of Medical Genetics, Purpan Hospital, CHU Toulouse, Toulouse, France
J Med Genet 49:373-9. 2012..Otocephaly or dysgnathia complex is characterised by mandibular hypoplasia/agenesis, ear anomalies, microstomia, and microglossia; the molecular basis of this developmental defect is largely unknown in humans...
- Mutation analysis of the STRA6 gene in isolated and non-isolated anophthalmia/microphthalmiaN Chassaing
Department of Medical Genetics, CHU Toulouse, Purpan Hospital, 31059, Toulouse, France
Clin Genet 83:244-50. 2013..This study suggests that STRA6 mutations are more likely to be identified in individuals with A/M and other abnormalities included in the PDAC spectrum, rather than in isolated A/M cases...
- GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotypeWilliam A Paznekas
Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA
Hum Mutat 30:724-33. 2009..Mutations resulting in ODDD occur in each of the nine domains of the Cx43 protein, and we review our functional experiments and those in the literature, examining the effects of 13 different Cx43 mutations upon gap junction activity...
- Tyrosine-dependent basolateral targeting of human connexin43-eYFP in Madin-Darby canine kidney cells can be disrupted by the oculodentodigital dysplasia mutation L90VJana Chtchetinin
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
FEBS J 276:6992-7005. 2009..These findings raise the possibility that some oculodentodigitial dysplasia-associated mutations contribute to disease by altering polarized targeting of Cx43...