{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:36:13Z","timestamp":1781109373053,"version":"3.54.1"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"8","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2005,2,22]]},"abstract":"<jats:p>\n                    Patent ductus arteriosus (PDA) is a common congenital heart disease that results when the ductus arteriosus, a muscular artery, fails to remodel and close after birth. A syndromic form of this disorder, Char syndrome, is caused by mutation in\n                    <jats:italic>TFAP2B<\/jats:italic>\n                    , the gene encoding a neural crest-derived transcription factor. Established features of the syndrome are PDA, facial dysmorphology, and fifth-finger clinodactyly. Disease-causing mutations are missense and are proposed to be dominant negative. Because only a small number of families have been reported, there is limited information on the spectrum of mutations and resulting phenotypes. We report the characterization of two kindreds (K144 and K145) with Char syndrome containing 22 and 5 affected members, respectively. Genotyping revealed linkage to\n                    <jats:italic>TFAP2B<\/jats:italic>\n                    in both families. Sequencing of\n                    <jats:italic>TFAP2B<\/jats:italic>\n                    demonstrated mutations in both kindreds that were not found among control chromosomes. Both mutations altered highly conserved bases in introns required for normal splicing as demonstrated by biochemical studies in mammalian cells. The abnormal splicing results in mRNAs containing frameshift mutations that are expected to be degraded by nonsense-mediated mRNA decay, resulting in haploinsufficiency; even if produced, the protein in K144 would lack DNA binding and dimerization motifs and would likely result in haploinsufficiency. Examination of these two kindreds for phenotypes that segregate with\n                    <jats:italic>TFAP2B<\/jats:italic>\n                    mutations identified several phenotypes not previously linked to Char syndrome. These include parasomnia and dental and occipital-bone abnormalities. The striking sleep disorder in these kindreds implicates TFAP2B-dependent functions in the normal regulation of sleep.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0409852102","type":"journal-article","created":{"date-parts":[[2005,1,31]],"date-time":"2005-01-31T20:24:43Z","timestamp":1107203083000},"page":"2975-2979","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":69,"title":["Syndromic patent ductus arteriosus: Evidence for haploinsufficient\n                    <i>TFAP2B<\/i>\n                    mutations and identification of a linked sleep disorder"],"prefix":"10.1073","volume":"102","author":[{"given":"Arya","family":"Mani","sequence":"first","affiliation":[{"name":"Departments of Medicine, Genetics, and Psychiatry, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, CT 06510; Department of Medicine, Mayo Clinic, Rochester, MN 55905; and Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84132-2101"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayaram","family":"Radhakrishnan","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Genetics, and Psychiatry, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, CT 06510; Department of Medicine, Mayo Clinic, Rochester, MN 55905; and Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84132-2101"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Farhi","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Genetics, and Psychiatry, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, CT 06510; Department of Medicine, Mayo Clinic, Rochester, MN 55905; and Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84132-2101"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khary S.","family":"Carew","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Genetics, and Psychiatry, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, CT 06510; Department of Medicine, Mayo Clinic, Rochester, MN 55905; and Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84132-2101"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole A.","family":"Warnes","sequence":"additional","affiliation":[{"name":"Departments of Medicine, Genetics, and Psychiatry, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, CT 06510; 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