title: Identification of a gene disrupted by inv(11)(q13.5;q25) in a patient with left-right axis malformation.
abstract: 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, symmetric liver, and abnormally lobulated spleen (polysplenia). This chromosomal rearrangement was inherited from the phenotypically normal father. We termed these regions DHTX-A (disrupted in heterotaxy)-- A at 11q13.5 and DHTX-B at 11q25. Here, we report the isolation and characterization of the inversion breakpoints and the gene that is disrupted by the DHTX-A breakpoint. The putative DHTX is identical to the UVRAG gene, which was originally identified as a gene that complements the UV sensitivity of xeroderma pigmentosum complementation group C. The 4-kb mRNA was found to be encoded by a large gene, at least 300 kb long, composed of 15 exons. The function of the gene product remains largely unknown. However, the near central portion of the UVRAG protein is predicted to contain a coiled-coil domain, which has been implicated in mediating protein-protein interactions. Southern analyses and fluorescence in situ hybridization (FISH) revealed that the DHTX-A breakpoint 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, respectively. Whole mount in situ hybridization also showed that the Uvrag gene is expressed in the presomite-stage embryo. Several hypotheses are discussed to explain the relationship between the chromosomal inversion and the accompanying phenotypes.
authors.affiliation: Department of Molecular Biology, Institute of Gerontology (ROUKEN), Nippon Medical School, Kawasaki, Kanagawa, Japan. ariiida@nms.ac.jp
authors.forename: A
authors.initials: A
authors.lastname: Iida
authors.forename: M
authors.initials: M
authors.lastname: Emi
authors.forename: R
authors.initials: R
authors.lastname: Matsuoka
authors.forename: E
authors.initials: E
authors.lastname: Hiratsuka
authors.forename: K
authors.initials: K
authors.lastname: Okui
authors.forename: H
authors.initials: H
authors.lastname: Ohashi
authors.forename: J
authors.initials: J
authors.lastname: Inazawa
authors.forename: Y
authors.initials: Y
authors.lastname: Fukushima
authors.forename: T
authors.initials: T
authors.lastname: Imai
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015139:Blotting, Southern; D002460:Cell Line; D002869:Chromosome Aberrations / Q000235:genetics*; D007446:Chromosome Inversion; D002880:Chromosomes, Human, Pair 11; D003001:Cloning, Molecular; D003914:Dextrocardia / Q000235:genetics; D005314:Embryonic and Fetal Development; D005091:Exons; D006330:Heart Defects, Congenital / Q000000981:diagnostic imaging / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D007438:Introns; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020161:Physical Chromosome Mapping; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011859:Radiography; D025521:Tumor Suppressor Proteins
chemical_list: D011506:Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C408122:UVRAG protein, human