RT Journal Article
SR Electronic
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
FD BMJ Publishing Group Ltd
SP jmedgenet-2017-105191
DO 10.1136/jmedgenet-2017-105191
A1 Elena Daniela Aflorei
A1 Benjamin Klapholz
A1 Chenghao Chen
A1 Serban Radian
A1 Anca Neluta Dragu
A1 Nina Moderau
A1 Chrisostomos Prodromou
A1 Paulo S Ribeiro
A1 Ralf Stanewsky
A1 Márta Korbonits
YR 2018
UL http://jmg.bmj.com/content/early/2018/04/08/jmedgenet-2017-105191.abstract
AB 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.