@article {Afloreijmedgenet-2017-105191, author = {Elena Daniela Aflorei and Benjamin Klapholz and Chenghao Chen and Serban Radian and Anca Neluta Dragu and Nina Moderau and Chrisostomos Prodromou and Paulo S Ribeiro and Ralf Stanewsky and M{\'a}rta Korbonits}, title = {In vivo bioassay to test the pathogenicity of missense human AIP variants}, elocation-id = {jmedgenet-2017-105191}, year = {2018}, doi = {10.1136/jmedgenet-2017-105191}, publisher = {BMJ Publishing Group Ltd}, 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 {\textquoteleft}unknown significance{\textquoteright}, with {\textquoteleft}pathogenic{\textquoteright} 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.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/early/2018/04/08/jmedgenet-2017-105191}, eprint = {https://jmg.bmj.com/content/early/2018/04/08/jmedgenet-2017-105191.full.pdf}, journal = {Journal of Medical Genetics} }