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Article: Monoallelic Mutations in CC2D1A Suggest a Novel Role in Human Heterotaxy and Ciliary Dysfunction

TitleMonoallelic Mutations in CC2D1A Suggest a Novel Role in Human Heterotaxy and Ciliary Dysfunction
Authors
Keywordscilia
exome
heterotaxy syndrome
isomerism
zebrafish
Issue Date2020
PublisherAmerican Heart Association. The Journal's web site is located at http://circgenetics.ahajournals.org/
Citation
Circulation: Genomic and Precision Medicine, 2020, v. 13 n. 6, p. 696-706 How to Cite?
AbstractBackground: 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. Methods: 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 alpha-tubulin. Results: We identified a significant enrichment of novel rare damaging mutations in the CC2D1A gene. Seven occurrences of CC2D1A mutations were found to affect 4 highly conserved amino acid residues of the protein. Functional analyses in the transcription activator-like effector nuclease-mediated 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 alpha-tubulin. These abnormalities were rescued by wild-type cc2d1a mRNA but not cc2d1a mutant mRNA, strongly suggesting a loss-of-function mechanism. On the other hand, overexpression of cc2d1a orthologous mutations cc2d1a P559L and cc2d1a G808V (orthologous to human CC2D1A P532L and CC2D1A G781V) did not affect embryonic development. Conclusions: Using a zebrafish model, we were able to establish a novel association of CC2D1A 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 CC2D1A in left-right patterning and ciliary dysfunction.
DescriptionHybrid open access
Persistent Identifierhttp://hdl.handle.net/10722/295903
ISSN
2023 Impact Factor: 6.0
2023 SCImago Journal Rankings: 2.670
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMa, ACH-
dc.contributor.authorMak, CCY-
dc.contributor.authorYeung, KS-
dc.contributor.authorPei, SLC-
dc.contributor.authorYing, D-
dc.contributor.authorYU, MHC-
dc.contributor.authorHasan, KMM-
dc.contributor.authorChen, X-
dc.contributor.authorChow, PC-
dc.contributor.authorCheung, YF-
dc.contributor.authorChung, BHY-
dc.date.accessioned2021-02-08T08:15:40Z-
dc.date.available2021-02-08T08:15:40Z-
dc.date.issued2020-
dc.identifier.citationCirculation: Genomic and Precision Medicine, 2020, v. 13 n. 6, p. 696-706-
dc.identifier.issn2574-8300-
dc.identifier.urihttp://hdl.handle.net/10722/295903-
dc.descriptionHybrid open access-
dc.description.abstractBackground: 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. Methods: 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 alpha-tubulin. Results: We identified a significant enrichment of novel rare damaging mutations in the CC2D1A gene. Seven occurrences of CC2D1A mutations were found to affect 4 highly conserved amino acid residues of the protein. Functional analyses in the transcription activator-like effector nuclease-mediated 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 alpha-tubulin. These abnormalities were rescued by wild-type cc2d1a mRNA but not cc2d1a mutant mRNA, strongly suggesting a loss-of-function mechanism. On the other hand, overexpression of cc2d1a orthologous mutations cc2d1a P559L and cc2d1a G808V (orthologous to human CC2D1A P532L and CC2D1A G781V) did not affect embryonic development. Conclusions: Using a zebrafish model, we were able to establish a novel association of CC2D1A 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 CC2D1A in left-right patterning and ciliary dysfunction.-
dc.languageeng-
dc.publisherAmerican Heart Association. The Journal's web site is located at http://circgenetics.ahajournals.org/-
dc.relation.ispartofCirculation: Genomic and Precision Medicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectcilia-
dc.subjectexome-
dc.subjectheterotaxy syndrome-
dc.subjectisomerism-
dc.subjectzebrafish-
dc.titleMonoallelic Mutations in CC2D1A Suggest a Novel Role in Human Heterotaxy and Ciliary Dysfunction-
dc.typeArticle-
dc.identifier.emailMak, CCY: ccymak@connect.hku.hk-
dc.identifier.emailYeung, KS: ksyyeung@hku.hk-
dc.identifier.emailChen, X: kxkchen@HKUCC-COM.hku.hk-
dc.identifier.emailCheung, YF: xfcheung@hku.hk-
dc.identifier.emailChung, BHY: bhychung@hku.hk-
dc.identifier.authorityCheung, YF=rp00382-
dc.identifier.authorityChung, BHY=rp00473-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1161/CIRCGEN.120.003000-
dc.identifier.pmid33196317-
dc.identifier.pmcidPMC7748040-
dc.identifier.scopuseid_2-s2.0-85097939119-
dc.identifier.hkuros321220-
dc.identifier.volume13-
dc.identifier.issue6-
dc.identifier.spage696-
dc.identifier.epage706-
dc.identifier.isiWOS:000598974000010-
dc.publisher.placeUnited States-

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