Mutations in Multidomain Protein MEGF8 Identify a Carpenter Syndrome Subtype Associated with Defective Lateralization

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dc.contributor.authorTwigg, Stephen R. F.
dc.contributor.authorLloyd, Deborah
dc.contributor.authorJenkins, Dagan
dc.contributor.authorElçioglu, Nurse E.
dc.contributor.authorCooper, Christopher D. O.
dc.contributor.authorAl-Sannaa, Nouriya
dc.contributor.authorAnnağur, Ali
dc.contributor.authorGillessen-Kaesbach, Gabriele
dc.contributor.authorHüning, Irina
dc.contributor.authorJ.L. Knight, Samantha
dc.contributor.authorGoodship, Judith A.
dc.contributor.authorKeavney, Bernard D.
dc.contributor.authorBeales, Philip L.
dc.contributor.authorGileadi, Opher
dc.contributor.authorMcGowan, Simon J.
dc.contributor.authorWilkie, Andrew O.M.
dc.date.accessioned2020-03-26T18:30:55Z
dc.date.available2020-03-26T18:30:55Z
dc.date.issued2012
dc.departmentSelçuk Üniversitesien_US
dc.description.abstractCarpenter syndrome is an autosomal-recessive multiple-congenital-malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet; many other clinical features occur, and the most frequent include obesity, umbilical hernia, cryptorchidism, and congenital heart disease. Mutations of RAB23, encoding a small GTPase that regulates vesicular transport, are present in the majority of cases. Here, we describe a disorder caused by mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning. We describe five affected individuals with similar dysmorphic facies, and three of them had either complete situs inversus, dextrocardia, or transposition of the great arteries; similar cardiac abnormalities were previously identified in a mouse mutant for the orthologous Megf8. The mutant alleles comprise one nonsense, three missense, and two splice-site mutations; we demonstrate in zebrafish that, in contrast to the wild-type protein, the proteins containing all three missense alterations provide only weak rescue of an early gastrulation phenotype induced by Megf8 knockdown. We conclude that mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members. We did not observe any subject with biallelic loss-of function mutations, suggesting that some residual MEGF8 function might be necessary for survival and might influence the phenotypes observed.en_US
dc.description.sponsorshipNational Institute for Health Research (NIHR) Biomedical Research Centre, OxfordNational Institute for Health Research (NIHR); Department of Health's NIHR Biomedical Research Centre's funding schemeNational Institute for Health Research (NIHR); European UnionEuropean Union (EU) [241955-2-SYSCILIA]; Wellcome TrustWellcome Trust [090532/Z/09/Z, 093329]; Newlife Foundation for Disabled Children [10-11/04]; British Heart FoundationBritish Heart Foundation [RG/08/012/25941, FS/10/008/28146]; Medical Research CouncilMedical Research Council UK (MRC) [G0601260]en_US
dc.description.sponsorshipWe are very grateful to the families for their participation in this study. We thank John O'Sullivan and Anna Topf for help with sample recruitment; Tracy Lester for coordinating diagnostic genetic analysis; Lorna Gregory and the staff at the High-Throughput Genomics facility at the Wellcome Trust Centre for Human Genetics (Oxford) for exome sequencing; Sue Butler, John Frank land, and Tim Rostron for help with cell culture and DNA sequencing; and Ekim Taskiran and Nurten Akarsu (Hacettepe University Medical Faculty, Department of Medical Genetics, Ankara, Turkey) for analysis of Turkish control samples. This work was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre, Oxford and received funding from the Department of Health's NIHR Biomedical Research Centre's funding scheme (to S.J.L.K. and A.O.M.W.), the European Union (FP7-HEALTH grant 241955-2-SYSCILIA to P.L.B.), the Wellcome Trust (University College London School of Life and Medical Sciences funding to D.J., Senior Research Fellowship in Clinical Science to P.L.B., Core Award 090532/Z/09/Z to S.J.L.K., and Project Grant 093329 to A.O.M.W and S.R.F.T.), and the Newlife Foundation for Disabled Children (10-11/04 to A.O.M.W. and S.R.F.T.). The views expressed in this publication are those of the authors and are not necessarily those of the Department of Health.en_US
dc.identifier.citationTwigg, S. R. F., Lloyd, D., Jenkins, D., Elçioğlu, N. E., Cooper, C. D. O., Al-Sannaa, N., Annağur, A., Gillessen-Kaesbach, G., Hüning, I., J.L. Knight, S., Goodship, J. A., Keavney, B. D., Beales, P. L., Gileadi, O., McGowan, S. J., Wilkie, A. O.M., (2012). Mutations in Multidomain Protein MEGF8 Identify a Carpenter Syndrome Subtype Associated with Defective Lateralization. American Journal of Human Genetics, 91(5), 897-905. http://dx.doi.org/10.1016/j.ajhg.2012.08.027
dc.identifier.doi10.1016/j.ajhg.2012.08.027en_US
dc.identifier.endpage905en_US
dc.identifier.issn0002-9297en_US
dc.identifier.issn1537-6605en_US
dc.identifier.issue5en_US
dc.identifier.pmid23063620en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage897en_US
dc.identifier.urihttps://dx.doi.org/10.1016/j.ajhg.2012.08.027
dc.identifier.urihttps://hdl.handle.net/20.500.12395/28251
dc.identifier.volume91en_US
dc.identifier.wosWOS:000311011400012en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.relation.ispartofAmerican Journal of Human Geneticsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.selcuk20240510_oaigen_US
dc.titleMutations in Multidomain Protein MEGF8 Identify a Carpenter Syndrome Subtype Associated with Defective Lateralizationen_US
dc.typeArticleen_US

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