期刊
JOURNAL OF MEDICAL GENETICS
卷 55, 期 8, 页码 522-529出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2017-105191
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资金
- Medical Research Council [MR/M018539/1]
- Pfizer UK [WS733753]
- Society for Endocrinology
- William Harvey Research Foundation [2011-5]
- Rosetrees Trust [M505] Funding Source: researchfish
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [P40OD018537] Funding Source: NIH RePORTER
- MRC [MR/M018539/1] Funding Source: UKRI
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 (CG1847(exon1_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 CG1847(exon1_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 CG1847(exon1_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.
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