Journal of medical genetics 2018 04 09() pii 10.1136/jmedgenet-2017-105191
Heterozygous germline loss-of-function mutations in the aryl hydrocarbon receptor-interacting protein gene () predispose to childhood-onset pituitary tumours. The pathogenicity of missense variants may pose difficulties for genetic counselling and family follow-up.
To develop an o system to test the pathogenicity of human mutations using the fruit fly .
We generated a null mutant of the orthologue, a gene located on the Xchromosome, which displayed lethality at larval stage in hemizygous knockout male mutants ( ). We tested human missense variants of ‘unknown significance’, with ‘pathogenic’ variants as positive control.
We found that human can functionally substitute for , as heterologous overexpression of human rescued male lethality, while a truncated version of did not restore viability. Flies harbouring patient-specific missense variants (p.C238Y, p.I13N, p.W73R and p.G272D) failed to rescue 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.
Our model represents a valuable tool to characterise putative disease-causing human variants and assist the genetic counselling and management of families carrying variants.