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.
