The overall aim of this project is to delineate the molecular mechanisms of heritable nonsyndromic cleft lip with or without cleft palate (CLP). The causes of facial clefting are extremely heterogeneous with CLP being part of greater than 100 recognizable syndromes but, more commonly, occurring as an isolated malformation. Within the latter group of disorders, called nonsyndromic CLP, we have recently shown genetic heterogeneity but have identified a homogeneous group of multigenerational families with autosomal dominant CLP. These multigenerational families have been well characterized, a crucial step towards elucidating the molecular mechanisms and the identification of the gene(s) responsible. In the initial study, we have shown that autosomal dominant gene is responsible for some of the cases of CLP and excluded tight linkage of CLP to transforming growth factor alpha which had previously been reported to be associated with heritable CLP. This proposal is for funds to continue our studies characterizing an autosomal dominant cleft lip and palate locus previously supported by a small grant (RO3) from the NIDR. In this continuing project, we propose to map an autosomal locus (or loci) causing nonsyndromic CLP using both "candidate gene" and "reverse genetics" approaches. We are in a unique position to accomplish this goal because we have identified homogeneous multigenerational families with autosomal dominant CLP, the molecular technology to localize the locus (loci) is available and a number of biologically pertinent candidate genes are available. Animal studies have recently provided new insights into craniofacial embryogenesis and the role of cell-cell interactions. From these observations, fourteen candidate genes have been selected for study by Sourthern gel methodology. Restriction fragment patterns from affected individuals will be examined for gross chromosomal rearrangements, such as deletions or insertions. Linkage to polymorphic sites will be tested in the multigenerational families to determine whether candidate genes are tightly linked to CLP. If tight linkage is excluded, the formation will be used in constructing linkage exclusion maps. Finally, if linkage to the candidate genes is excluded, a systemic search of the genome will be undertaken using variable number tandem repeat probes, multiple restriction site polymorphisms, and polymerase chain reaction detectable polymorphisms to detect linkage to a CLP locus. An exclusion map developed from previous linkage studies and loci excluded in this study will be used to target areas for study. Information derived from this study will provide a basis for 1) elucidating the specific mutation(s) causing heritable CLP in these multigenerational families, 2) characterizing the pathogenesis of the disorder and, 3) providing specific counseling information for families at risk for CLP. Information about heritable CLP may also lead to an understanding of the etiologic mechanisms involved in sporadic nonsyndromic CLP and other disorders resulting from abnormalities of embryogenesis.
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