description): A portion of the molecular pathway has begun to emerge from studies of chick, Xenopus, and mouse, in which nodal, lefty, HNF3beta, and other genes have been implicated in left-right axis development. In humans, normal left-right asymmetry (situs solitus) randomizes in approximately 1/20,000 live births. Affected individuals display an anatomic arrangement, situs ambiguus, most commonly characterized by severe heart malformations, splenic abnormalities, and malposition of the abdominal viscera. Although most cases are sporadic, families with autosomal and X-linked transmission have been described. Recently the investigators have identified by positional cloning a gene, HTX1, associated with X-linked situs abnormalities. Clinical observation and preliminary analysis suggest that HTX1 mutations will account for a relatively small percentage of situs cases. The investigators hypothesize that mutations in human homologues of other genes identified in vertebrate model systems will underlie a significant portion of the remainder. Observations in mice also suggest that digenic mutations may account for situs abnormalities in some individuals. In order to test these hypotheses, the investigators propose a pilot project to clone and characterize the human homologues of nodal, lefty, and HNF3beta. Mutation analysis for these genes will be performed in 76 sporadic cases of situs abnormalities that have been collected to date. Mutation analysis also will be carried out in selected individuals from the 24 families in which left-right asymmetry defects segregate in a pattern consistent with autosomal inheritance. The applicant contends that these studies will provide essential preliminary data regarding the frequency and extent of mutations in vertebrate left-right axis genes that are associated with human situs abnormalities.
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