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bioassay to test the pathogenicity of missense human variants.

bioassay to test the pathogenicity of missense human  variants.
Author Information (click to view)

Aflorei ED, Klapholz B, Chen C, Radian S, Dragu AN, Moderau N, Prodromou C, Ribeiro PS, Stanewsky R, Korbonits M,


Aflorei ED, Klapholz B, Chen C, Radian S, Dragu AN, Moderau N, Prodromou C, Ribeiro PS, Stanewsky R, Korbonits M, (click to view)

Aflorei ED, Klapholz B, Chen C, Radian S, Dragu AN, Moderau N, Prodromou C, Ribeiro PS, Stanewsky R, Korbonits M,

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Journal of medical genetics 2018 04 09() pii 10.1136/jmedgenet-2017-105191

Abstract
BACKGROUND
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.

OBJECTIVE
To develop an o system to test the pathogenicity of human mutations using the fruit fly .

METHODS
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.

RESULTS
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.

CONCLUSION
Our model represents a valuable tool to characterise putative disease-causing human variants and assist the genetic counselling and management of families carrying variants.

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