Identification of a gene disrupted by inv(11)(q13.5;q25) in a patient withleft-right axis malformation

An inv(11)(q13.5;q25) inversion was previously identified in a 9-month-old male patient with complex cyanotic heart defects, altered lung lobation, sy m metric liver, and abnormally lobulated spleen (polysplenia). This chromos omal rearrangement was inherited from the phenotypically normal father. We termed these regions DHTX-A (disrupted in heterotaxy)- A at 11q13.5 and DHT X-B at 11q25. Here, we report the isolation and characterization of the inv ersion breakpoints and the gene that is disrupted by the DHTX-A breakpoint. The putative DHTX is identical to the UVRAG gene, which was originally ide ntified as a gene that complements the UV sensitivity of xeroderma pigmento sum complementation group C. The 4-kb mRNA was found to be encoded by a lar ge gene, at least 300 kb long, composed of 15 exons. The function of the ge ne product remains largely unknown. However, the near central portion of th e UVRAG protein is predicted to contain a coiled-coil domain, which has bee n implicated in mediating protein-protein interactions. Southern analyses a nd fluorescence in situ hybridization (FISH) revealed that the DHTX-A break point in the patient and his father lies within the intron between exons 6 and 7 of UVRAG. Northern blot analysis indicated strong expression in human fetal and adult tissues and in mouse embryonic day-7 and adult tissues, re spectively. Whole mount in situ hybridization also showed that the Uvrag ge ne is expressed in the presomite-stage embryo. Several hypotheses are discu ssed to explain the relationship between the chromosomal inversion and the accompanying phenotypes.