dc.contributor.author | Aflorei, ED | en_US |
dc.contributor.author | Klapholz, B | en_US |
dc.contributor.author | Chen, C | en_US |
dc.contributor.author | Radian, S | en_US |
dc.contributor.author | Dragu, AN | en_US |
dc.contributor.author | Moderau, N | en_US |
dc.contributor.author | Prodromou, C | en_US |
dc.contributor.author | Ribeiro, PS | en_US |
dc.contributor.author | Stanewsky, R | en_US |
dc.contributor.author | Korbonits, M | en_US |
dc.date.accessioned | 2018-09-26T15:38:30Z | |
dc.date.available | 2018-03-01 | en_US |
dc.date.issued | 2018-08 | en_US |
dc.date.submitted | 2018-04-16T09:20:48.743Z | |
dc.identifier.other | 10.1136/jmedgenet-2017-105191 | |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/45365 | |
dc.description.abstract | BACKGROUND: 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.sponsorship | Grant 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.extent | 522 - 529 | en_US |
dc.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | J Med Genet | en_US |
dc.rights | Creative Commons Attribution License | |
dc.subject | AIP | en_US |
dc.subject | FIPA | en_US |
dc.subject | drosophila melanogaster | en_US |
dc.subject | pathogenic genetic variant | en_US |
dc.subject | pituitary adenoma | en_US |
dc.title | In vivo bioassay to test the pathogenicity of missense human AIP variants. | en_US |
dc.type | Article | |
dc.rights.holder | Article author(s) (or their employer(s) | |
dc.identifier.doi | 10.1136/jmedgenet-2017-105191 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/29632148 | en_US |
pubs.issue | 8 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 55 | en_US |
dcterms.dateAccepted | 2018-03-01 | en_US |