Studying novel neurodevelopmental diseases associated with genome instability

Project Overview:

Defective DNA repair is a major driver of genetic instability and cancer development. This PhD project, based in Professor Stewart’s laboratory, will investigate how cells detect and repair DNA damage, and how defects in these processes give rise to human disease. By studying rare inherited disorders, the project aims to generate fundamental insights into the DNA damage response and its role in conditions such as neurodegeneration, developmental abnormalities, immune dysfunction, infertility, and cancer.

Research Focus:

The Stewart laboratory has extensive expertise in the molecular characterisation of rare genetic disorders associated with defective DNA repair and abnormal DNA replication, including Ataxia-Telangiectasia, Fanconi Anaemia, Seckel Syndrome, and Microcephalic Primordial Dwarfism. Building on this work, the project will focus on newly identified inherited syndromes linked to genome instability, arising from defects in DNA replication, replication stress responses, or specific DNA repair pathways.
Using patient-derived cell models and state-of-the-art molecular and cellular biology techniques, you will define how specific gene variants disrupt genome maintenance and drive disease. This will involve a combination of genetic, biochemical, and cell biology approaches, offering comprehensive training in cutting-edge research methods.

Training and Impact:

This project provides an excellent opportunity to gain expertise in genome stability, human genetics, and disease mechanisms within a collaborative and translational research environment. Findings from this work will not only contribute to improved genetic diagnosis, clinical management, and counselling for patients, but may also identify novel cellular pathways and targets relevant to more common diseases, including cancer.

Funding notes:

Self-funding must include a reasonable level of costs to cover yearly laboratory bench fees.

References:

1. Reynolds JJ, Bicknell LS, Carroll P, Higgs MR, Shaheen R, Murray JE, Papadopoulos DK, Leitch A, Murina O, Tarnauskaitė Ž, Wessel SR, Zlatanou A, Vernet A, Kriegsheim A, Mottram RMA, Logan CV, Bye H, Li Y, Brean A, Maddirevula S, Challis RC, Skouloudaki K, Almoisheer A, Alsaif HS, Amar A, Prescott NJ, Bober MB, Duker A, Faqeih E, Seidahmed MZ, Tala SA, Alswaid A, Ahmed S, Al-Aama JY, Altmüller J, Balwi MA, Brady AF, Chessa L, Cox H, Fischetto R, Heller R, Henderson BD, Hobson E, Nürnberg P, Percin EF, Peron S, Spaccini L, Quigley AJ, Thakur S, Wise CA, Yoon G, Alnemer M, Tomancak P, Yigit G, Taylor AMR, Reijns MAM, Simpson MA, Cortez D, Alkuraya FS, Mathew CG, Jackson AP, Stewart GS. (2017). Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nature Genet. 49:537-549

2. Baxley RM, Leung W, Schmit MM, Matson JP, Oram MK, Wang L, Yin L, Hedberg J, Rogers CB, Harvey AJ, Basu D, Hendrickson EA, Mace EM, Orange JS, Aihara H, Stewart GS, Blair E, Gowen Cook J, Bielinsky AK. (2020). Bi-allelic MCM10 mutations cause telomere shortening with immune dysfunction and cardiomyopathy. Nature Commun. 12:1626

3. Abu-Libdeh B, Jhujh SS, Dhar S, Sommers JA, Datta A, Longo GMC, Grange LJ, Reynolds JJ, Cooke SL, McNee GS, Hollingworth R, Woodward BL, Ganesh AN, Smerdon SJ, Nicolae CM, Durlacher-Betzer K, Molho-Pessach V, Abu-Libdeh A, Meiner V, Moldovan G-L, Roukos V, Harel T, Brosh Jr. RM, Stewart GS. (2022). RECON Syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1. J Clin Invest. 132:e147301

4. Grange LJ, Reynolds JJ, Ullah F, Isidor B, Shearer RF, Latypova X, Baxley RM, Oliver AW, Ganesh AN, Cooke SL, Jhujh SS, McNee GS, Hollingworth R, Higgs MR, Natsume T, Khan T, Martos-Moreno GÁ, Chupp S, Mathew CG, Parry D, Simpson MA, Nahavandi N, Yüksel Z, Drasdo M, Kron A, Vogt P, Jonasson A, Seth SA, Gonzaga-Jauregui C, Brigatti KW, Stegmann APA, Kanemaki M, Josifova D, Uchiyama Y, Oh Y, Morimoto A, Osaka H, Ammous Z, Argente J, Matsumoto N, Stumpel CTRM, Taylor AMR, Jackson AP, Bielinsky A-K, Mailand N, Le Caignec C, Davis EE, Stewart GS. (2022). Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy. Nature Commun. 13:6664

5. Woodward BL, Lahiri S, Chauhan AS, Garcia MR, Goodley L, Clarke TL, Pal M, Agathanggelou A, Jhujh SS, Ganesh AN, Hollins, FM, Galassi Defore V, Maroofian R, Efthymiou S, Meinhardt A, Mathew CG, Simpson MA, Mefford HC, Faqeih EA, Rosenweig SD, Volpi S, Di Matteo G, Cancrini C, Scardamaglia A, Shackley F, Davies EG, Ibrahim S, Arkwright P, Zaki MS, Stankovic T, Taylor AMR, Mazur AJ, Di Donato N, Houlden H, Rothenberg E, Stewart GS. (2025). Inherited deficiency of DIAPH1 identifies a DNA double strand break repair pathway regulated by -actin. Nature Commun. 16:4491