Investigating the pathogenic impact of mutations in TICRR and MTBP as the underlying genetic cause of a novel developmental disorder in children

Jhujh, Satpal Singh ORCID: 0000-0001-5766-659X (2020). Investigating the pathogenic impact of mutations in TICRR and MTBP as the underlying genetic cause of a novel developmental disorder in children. University of Birmingham. Ph.D.

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Abstract

Several heritable human disorders arise from abnormalities in the DNA replication stress response such as ATR/ATRIP-Seckel Syndrome and Meier-Gorlin Syndrome (MGS). These disorders are hallmarked by a combination of common phenotypes such as microcephaly, growth restriction, skeletal abnormalities and impaired cellular response to replication stress.

Deficiencies in both TICRR/Treslin and its binding partner MTBP have not been previously linked to replication stress associated disorders. Six patients have been identified with biallelic mutations in either TICRR/Treslin or MTBP. The protein products of these genes are known to be binding partners and have roles in DNA replication initiation through interaction with TopBP1. The patients all have presented with clinical phenotypes consistent with replication stress disorders; showing particularly significant overlap with MGS. The patients all have severe inter-uterine growth restriction and an array of growth defects; including microcephaly, craniosynostosis, facial dysmorphia, hypoplastic thumbs, anorectal malformations, and dilated cardiomyopathy.

Cells derived from these patients exhibited increased levels of spontaneous replication stress. Utilising the DNA fibre assay and immunofluorescence we have been able to show that there is increased replication fork stalling and formation of G1-53BP1 bodies. Additionally, we show that this unresolved replication stress manifests itself as increased genome instability as chromosomal aberrations and micronuclei formation. These phenotypes are exacerbated upon challenge with known genotoxic stress causing agents such as aphidicolin (APH), hydroxyurea (HU) and Mitomycin C (MMC). We hypothesise that the clinical phenotype observed in these patients is the result of increased replication stress during embryogenesis. This leads to a global decrease in cellular proliferative capacity resulting in a reduction in the number of cells produced during embryogenesis and growth defects in the child.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):