Project: Research project

Project Details


Oculoauriculovertebral dysplasia (OAV) is a disorder characterized by ear
malformations, jaw asymmetry, eye abnormalities and anomalies of the
cervical spine. It has recently been shown that this disorder is autosomal
dominantly inherited in some families (Kaye et al., 1990). The genetic
basis for the malformations observed in patients with OAV is unknown.
Clinical and experimental data have suggested candidate genes which may be
involved in this dysplasia. Retinoic acid, a vitamin A metabolite, has been shown to produce
craniofacial anomalies mimicking OAC in a high percentage of infants
exposed to the agent in utero. The action of vitamin A and its metabolites
appear to be mediated by three specific receptors in the developing embryo.
A mutation in the gene coding for one of these receptors might be directly
responsible for altered morphogenesis, such as is seen in patients with
OAV. Alternatively, retinoic acid may induce other genes important in
morphogenesis. Retinoic acid induces the expression of the homeobox (HOX) genes in
embryonic carcinoma cells. The homeoboxes are a highly conserved gene
family which were first identified as regulators of embryonic development
in Drosophila melanogaster. By sequence homology, HOX genes have been
isolated from both mouse and man. Experimental evidence from transgenic
mice implies that an overexpression of one HOX gene, Hox-1.1, results in
animals which have multiple craniofacial anomalies. These animals
demonstrate a phenotype which mimics retinoic acid embryopathy and OAV. The basic defects of malformation syndromes are elusive. This dysplasia
provides an opportunity to understand how an alteration in a single gene
can produce such syndromes. By performing linkage analysis in OAV families
with markers for the HOX and retinoic acid loci, we can determine if these
genes are altered in OAV. Eight families of children with OAV will be studied. In each family, OAV
is segregating in an autosomal dominant pattern. Thus these families are
ideal for testing the role of these candidate genes in this disease. To
begin this analysis, blood samples will be obtained from patients with OAV
and from informative family members. Lymphoblastoid cell lines will be
established from each sample. DNA will be isolated from the cell lines and
analyzed with polymorphic markers from the candidate genes. These data
will be utilized to establish the role of these genes in OAV. If linkage is established with the candidate genes under investigation,
then future studies will focus on identification of specific mutations. If
linkage is disproved, then future studies will focus on identification of
other loci which are linked to the autosomal dominant gene in the families
under investigation. The long term goal of the research is to identify an
abnormal gene associated with craniofacial dysmorphogenesis and to
elucidate its mutation.
Effective start/end date4/1/913/31/92


  • National Institutes of Health


  • Medicine(all)
  • Dentistry(all)


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