{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T20:31:58Z","timestamp":1779395518026,"version":"3.53.1"},"reference-count":63,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Human heterotaxy is a group of congenital disorders characterized by misplacement of one or more organs according to the left-right axis. The genetic causes of human heterotaxy are highly heterogeneous.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>We performed exome sequencing in a cohort of 26 probands with heterotaxy followed by gene burden analysis for the enrichment of novel rare damaging mutations. Transcription activator-like effector nuclease was used to generate somatic loss-of-function mutants in a zebrafish model. Ciliary defects were examined by whole-mount immunostaining of acetylated \u03b1-tubulin.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We identified a significant enrichment of novel rare damaging mutations in the\n              <jats:italic>CC2D1A<\/jats:italic>\n              gene. Seven occurrences of\n              <jats:italic>CC2D1A<\/jats:italic>\n              mutations were found to affect 4 highly conserved amino acid residues of the protein. Functional analyses in the transcription activator-like effector nuclease\u2013mediated zebrafish knockout models were performed, and heterotaxy phenotypes of the cardiovascular and gastrointestinal systems in both somatic and germline mutants were observed. Defective cilia were demonstrated by whole-mount immunostaining of acetylated \u03b1-tubulin. These abnormalities were rescued by wild-type\n              <jats:italic>cc2d1a<\/jats:italic>\n              mRNA but not\n              <jats:italic>cc2d1a<\/jats:italic>\n              mutant mRNA, strongly suggesting a loss-of-function mechanism. On the other hand, overexpression of\n              <jats:italic>cc2d1a<\/jats:italic>\n              orthologous mutations\n              <jats:italic>cc2d1a<\/jats:italic>\n              P559L and\n              <jats:italic>cc2d1a<\/jats:italic>\n              G808V (orthologous to human\n              <jats:italic>CC2D1A<\/jats:italic>\n              P532L and\n              <jats:italic>CC2D1A<\/jats:italic>\n              G781V) did not affect embryonic development.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Using a zebrafish model, we were able to establish a novel association of\n              <jats:italic>CC2D1A<\/jats:italic>\n              with heterotaxy and ciliary dysfunction in the F2 generation via a loss-of-function mechanism. Future mechanistic studies are needed for a better understanding of the role of\n              <jats:italic>CC2D1A<\/jats:italic>\n              in left-right patterning and ciliary dysfunction.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.120.003000","type":"journal-article","created":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T17:00:22Z","timestamp":1605546022000},"source":"Crossref","is-referenced-by-count":10,"title":["Monoallelic Mutations in\n            <i>CC2D1A<\/i>\n            Suggest a Novel Role in Human Heterotaxy and Ciliary Dysfunction"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4800-2844","authenticated-orcid":true,"given":"Alvin Chun Hang","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong Special Administrate Region, China (A.C.H., K.M.M.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6934-6518","authenticated-orcid":true,"given":"Christopher Chun Yu","family":"Mak","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Kong Kong, Hong Kong Special Administrate Region, China (C.C.Y.M., K.S.Y., S.L.C.P., D.Y., M.H.C.Y., P.C.C., Y.F.C., B.H.Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1480-3619","authenticated-orcid":true,"given":"Kit San","family":"Yeung","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Kong Kong, Hong Kong Special Administrate Region, China (C.C.Y.M., K.S.Y., S.L.C.P., D.Y., M.H.C.Y., P.C.C., Y.F.C., B.H.Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1335-5380","authenticated-orcid":true,"given":"Steven Lim Cho","family":"Pei","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Kong Kong, Hong Kong Special Administrate Region, China (C.C.Y.M., K.S.Y., S.L.C.P., D.Y., M.H.C.Y., P.C.C., Y.F.C., B.H.Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingge","family":"Ying","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Kong Kong, Hong Kong Special Administrate Region, China (C.C.Y.M., K.S.Y., S.L.C.P., D.Y., M.H.C.Y., P.C.C., Y.F.C., B.H.Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mullin Ho Chung","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Kong Kong, Hong Kong Special Administrate Region, China (C.C.Y.M., K.S.Y., S.L.C.P., D.Y., M.H.C.Y., P.C.C., Y.F.C., B.H.Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5724-8347","authenticated-orcid":true,"given":"Kazi Md Mahmudul","family":"Hasan","sequence":"additional","affiliation":[{"name":"Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong Special Administrate Region, China (A.C.H., K.M.M.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2069-6634","authenticated-orcid":true,"given":"Xiangke","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (X.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pak Cheong","family":"Chow","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Kong Kong, Hong Kong Special Administrate Region, China (C.C.Y.M., K.S.Y., S.L.C.P., D.Y., M.H.C.Y., P.C.C., Y.F.C., B.H.Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7279-4992","authenticated-orcid":true,"given":"Yiu Fai","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Kong Kong, Hong Kong Special Administrate Region, China (C.C.Y.M., K.S.Y., S.L.C.P., D.Y., M.H.C.Y., P.C.C., Y.F.C., B.H.Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7044-5916","authenticated-orcid":true,"given":"Brian Hon 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