{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T06:56:17Z","timestamp":1792738577634,"version":"4.5.0"},"reference-count":26,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Nearly one in 100 live births presents with congenital heart defects (CHD). CHD is frequently associated with laterality defects, such as\n              <jats:italic>situs inversus<\/jats:italic>\n              , a mirrored positioning of internal organs. Body laterality is established by a complex process: monocilia at the embryonic left-right organizer facilitate both the generation and sensing of a leftward fluid flow. This induces the conserved left-sided Nodal signaling cascade to initiate asymmetrical organogenesis. Primary ciliary dyskinesia originates from dysfunction of motile cilia, causing symptoms such as chronic sinusitis, bronchiectasis and frequently\n              <jats:italic>situs inversus totalis<\/jats:italic>\n              . The most frequently mutated gene in primary ciliary dyskinesia,\n              <jats:italic>DNAH5<\/jats:italic>\n              is associated with randomization of body asymmetry resulting in\n              <jats:italic>situs inversus totalis<\/jats:italic>\n              in half of the patients; however, its relation to CHD occurrence in humans has not been investigated in detail so far.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              We performed genotype\/phenotype correlations in 132 patients with primary ciliary dyskinesia carrying disease-causing\n              <jats:italic>DNAH5<\/jats:italic>\n              mutations, focusing on\n              <jats:italic>situs<\/jats:italic>\n              defects and CHD. Using high-speed video microscopy-, immunofluorescence-, and in situ hybridization analyses, we investigated the initial steps of left-right axis establishment in embryos of a\n              <jats:italic>Dnah5<\/jats:italic>\n              -mutant mouse model.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              In patients with primary ciliary dyskinesia carrying disease-causing\n              <jats:italic>DNAH5<\/jats:italic>\n              mutations, 65.9% (87\/132) had laterality defects: 88.5% (77\/87) presented with\n              <jats:italic>situs inversus totalis<\/jats:italic>\n              , 11.5% (10\/87) presented with\n              <jats:italic>situs ambiguus<\/jats:italic>\n              ; and 6.1% (8\/132) presented with CHD. In\n              <jats:italic>Dnah5<\/jats:italic>\n              <jats:sup>mut\/mut<\/jats:sup>\n              mice, embryonic left-right organizer monocilia lack outer dynein arms resulting in immotile cilia, impaired flow at the left-right organizer, and randomization of Nodal signaling with normal, reversed or bilateral expression of key molecules.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              For the first time, we directly demonstrate the disease-mechanism of laterality defects linked to DNAH5 deficiency at the molecular level during embryogenesis. We highlight that mutations in\n              <jats:italic>DNAH5<\/jats:italic>\n              are not only associated with classical randomization of left-right body asymmetry but also with severe laterality defects including CHD.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.119.002686","type":"journal-article","created":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T19:00:36Z","timestamp":1574190036000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["Randomization of Left-Right Asymmetry and Congenital Heart Defects"],"prefix":"10.1161","volume":"12","author":[{"given":"Tabea","family":"N\u00f6the-Menchen","sequence":"first","affiliation":[{"name":"Department of General Pediatrics, University Children\u2019s Hospital Muenster, 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