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dc.contributor.authorAflorei, EDen_US
dc.contributor.authorKlapholz, Ben_US
dc.contributor.authorChen, Cen_US
dc.contributor.authorRadian, Sen_US
dc.contributor.authorDragu, ANen_US
dc.contributor.authorModerau, Nen_US
dc.contributor.authorProdromou, Cen_US
dc.contributor.authorRibeiro, PSen_US
dc.contributor.authorStanewsky, Ren_US
dc.contributor.authorKorbonits, Men_US
dc.date.accessioned2018-09-26T15:38:30Z
dc.date.available2018-03-01en_US
dc.date.issued2018-08en_US
dc.date.submitted2018-04-16T09:20:48.743Z
dc.identifier.other10.1136/jmedgenet-2017-105191
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/45365
dc.description.abstractBACKGROUND: Heterozygous germline loss-of-function mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP) predispose to childhood-onset pituitary tumours. The pathogenicity of missense variants may pose difficulties for genetic counselling and family follow-up. OBJECTIVE: To develop an in vivo system to test the pathogenicity of human AIP mutations using the fruit fly Drosophila melanogaster. METHODS: We generated a null mutant of the Drosophila AIP orthologue, CG1847, a gene located on the Xchromosome, which displayed lethality at larval stage in hemizygous knockout male mutants (CG1847exon1_3 ). We tested human missense variants of 'unknown significance', with 'pathogenic' variants as positive control. RESULTS: We found that human AIP can functionally substitute for CG1847, as heterologous overexpression of human AIP rescued male CG1847exon1_3 lethality, while a truncated version of AIP did not restore viability. Flies harbouring patient-specific missense AIP variants (p.C238Y, p.I13N, p.W73R and p.G272D) failed to rescue CG1847exon1_3 mutants, while seven variants (p.R16H, p.Q164R, p.E293V, p.A299V, p.R304Q, p.R314W and p.R325Q) showed rescue, supporting a non-pathogenic role for these latter variants corresponding to prevalence and clinical data. CONCLUSION: Our in vivo model represents a valuable tool to characterise putative disease-causing human AIP variants and assist the genetic counselling and management of families carrying AIP variants.en_US
dc.description.sponsorshipGrant number MR/M018539/1 granted by Medical Research Council; WS733753 granted by Pfizer UK, November 2014 Early Career Grant awarded by Society for Endocrinology; #2011-5 awarded by William Harvey Research Foundation.en_US
dc.format.extent522 - 529en_US
dc.languageengen_US
dc.language.isoenen_US
dc.relation.ispartofJ Med Geneten_US
dc.rightsCreative Commons Attribution License
dc.subjectAIPen_US
dc.subjectFIPAen_US
dc.subjectdrosophila melanogasteren_US
dc.subjectpathogenic genetic varianten_US
dc.subjectpituitary adenomaen_US
dc.titleIn vivo bioassay to test the pathogenicity of missense human AIP variants.en_US
dc.typeArticle
dc.rights.holderArticle author(s) (or their employer(s)
dc.identifier.doi10.1136/jmedgenet-2017-105191en_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/29632148en_US
pubs.issue8en_US
pubs.notesNot knownen_US
pubs.publication-statusPublisheden_US
pubs.volume55en_US
dcterms.dateAccepted2018-03-01en_US


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