TY - JOUR T1 - <em>In vivo</em> bioassay to test the pathogenicity of missense human <em>AIP</em> variants JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2017-105191 SP - jmedgenet-2017-105191 AU - Elena Daniela Aflorei AU - Benjamin Klapholz AU - Chenghao Chen AU - Serban Radian AU - Anca Neluta Dragu AU - Nina Moderau AU - Chrisostomos Prodromou AU - Paulo S Ribeiro AU - Ralf Stanewsky AU - Márta Korbonits Y1 - 2018/04/09 UR - http://jmg.bmj.com/content/early/2018/04/08/jmedgenet-2017-105191.abstract N2 - 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. ER -