Identifying suppressor mutations of ATR-X and ADNP syndromes using a novel CRISPR-based screening method in mice (360G-Wellcome-210913_Z_18_Z)

£250,000

The recent Deciphering Developmental Disorders Study found that mutations in genes encoding epigenetics proteins are a primary cause of intellectual disability. These disorders are incurable and their underlying mechanisms remain elusive. Intriguingly, varying symptom severity has been described in patients with the same causative mutations for a number of these disorders and phenotypes displayed in some mouse models are strain-dependent. To search for secondary mutations that suppress phenotypes in mouse models of the neurological disorder, Rett syndrome, Monica Justice’s lab performed a genome-wide screen by inducing random mutations with the chemical mutagen ENU. I aim to take advantage of recent advances in CRISPR/Cas9 technology to develop a CRISPR-based screening method. This method will simplify isolation of modifying mutations, greatly reduce the number of animals required and can be adapted for recessive screening. I will use this method to screen for suppressors of two neurological disorders that are predicted to be modifiable: ATR-X and ADNP syndromes. Both causative genes encode epigenetic proteins: ATRX is a chromatin remodelling ATPase and ADNP is a putative transcription factor. I hope that the ‘hits’ obtained in these screens will help us to better understand ATRX/ADNP protein function and open up therapeutic avenues for patients.

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Grant Details

Amount Awarded 250000
Applicant Surname Tillotson
Approval Committee Basic Science Interview Committee
Award Date 2018-04-24T00:00:00+00:00
Financial Year 2017/18
Grant Programme: Title Sir Henry Wellcome Postdoctoral Fellowship
Internal ID 210913/Z/18/Z
Lead Applicant Dr Rebekah Tillotson
Partnership Value 250000
Planned Dates: End Date 2023-12-18T00:00:00+00:00
Planned Dates: Start Date 2018-11-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East
Sponsor(s) Prof Douglas Higgs