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Bicknell Laboratory: Human Genetics

Overview

Bicknell DNA replication figureDr Louise Bicknell's laboratory focuses on understanding how the genetic variation present in our genomes can shape or influence genetic conditions. The lab harnesses the power of mutations underlying Mendelian disorders to gain biological insight into our development and lifetime health.

The laboratory has two main themes:

  • Identifying the causes of rare Mendelian disorders using exome / genome sequencing and learning about the biology connecting the causative gene with the clinical syndromes
  • Investigating how additional genetic variation in our genomes can influence the clinical consequence of a genetic mutation to explain differences between patients with the same genetic condition

A particular focus of the lab is on Meier-Gorlin syndrome (MGS), where disruption of the earliest stages of DNA replication leads to a specific syndrome of short stature, small ears, and absent kneecaps. The lab investigates the biological roles of both established and novel MGS genes using genomic, cellular and developmental biology approaches, including utilising CRISPR in Xenopus laevis to model disease mutations (in collaboration with Dr Caroline Beck, Department of Zoology).

A new project initiated in the Bicknell Lab, in collaboration with the Beck Lab, is a focus on New Zealanders with microcephaly (reduced brain size). We are undertaking exome sequencing of families in which a child is affected by microcephaly, and will study the developmental mechanisms through CRISPR editing in Xenopus laevis. We greatly appreciate the support for this project from the Cliff Broad Family Trust, administered through the Neurological Foundation of New Zealand.

Dr Bicknell's laboratory is supported by a Rutherford Discovery Fellowship, the Marsden Fund, and the University of Otago.

Clinicians or scientists interested in collaborating are encouraged to email Louise.

Students interested in undertaking a research project should get in touch with Louise.

Email louise.bicknell@otago.ac.nz

Our key people

Dr Louise Bicknell - Principal Investigator, Rutherford Discovery Fellow

Louise BicknellLouise completed her PhD with Professor Stephen Robertson, University in Otago (2007), examining the genetic contributors to joint dislocation in children. She undertook a postdoctoral fellowship with Professor Andrew Jackson, University of Edinburgh (2008-2015), the last three years of which were personally supported by Medical Research Scotland. This research focused on characterising novel causes of microcephalic primordial dwarfism, a rare genetic disorder of extreme global growth failure.

Amongst her successes, she successfully identified five novel genes underlying Meier-Gorlin syndrome, a disorder of short stature, small ears, and absent kneecaps (Bicknell et al., 2011a, Nature Genetics; Bicknell et al., 2011b, Nature Genetics) and has continued this interest at Otago.

The clinical differences seen in children with the same genetic syndrome piqued her curosity, and she now also investigates the role that additional background genetic variation may play in shaping disease development and progression.

Dr Karen Knapp - Postdoctoral Research FellowKaren Knapp

Karen completed her PhD in the research group of Professor Norbert Sträter at Leipzig University, Germany (2010), carrying out research involving the biochemical and structural characterization of a cancer drug target (CD73). She went on to carry out postdoctoral research within the Biochemistry Department at the University of Otago (2010-2013), involving the structural characterization of viral and host protein complexes. This was followed by further postdoctoral research at the North West Cancer Research Institute, Bangor University, UK (2013-2015), investigating DNA repair mechanisms and their role in cancer. In 2016 Karen joined the Bicknell Lab as a postdoctoral research fellow, and is carrying out research which focuses on identifying and characterising novel DNA replication components, in which mutations cause the rare Mendelian disorder, Meier-Gorlin syndrome (MGS).

Dr Danielle Jenkins - Assistant Research Fellow

Danielle completed her PhD with Associate Professor Stephen Bunn in the Department of Anatomy and Centre for Neuroendocrinology, University of Otago (2017). During this time, her research focused on interactions between the cytokine interleukin-6 and the adrenal medulla during immune challenge. In 2018, Danielle joined the Bicknell lab as an Assistant Research Fellow where she is investigating genetic mutations associated with microcephaly, and the involvement of these genes in neural development.​

Students

Rosie Sullivan - MSc Genetics student

Rosie completed her Bachelor of Science, majoring in Genetics, at the University of Otago in 2017. Rosie joined the Bicknell Lab in 2018 as a Masters student. Her project is to use CRISPR / Cas9 genome editing to knock-in mutations involved in Meier-Gorlin syndrome into hTERT-RPE1 cells, and to use these cells to look at the cellular consequences of these mutations.

Matthew Reily-Bell - MSc thesis student

Matt completed his Bachelor of Science (Honours) 1st class, majoring in Genetics, at the University of Otago in 2017. In collaboration with Associate Professor Caroline Beck, Matt’s Masters project is to utilise CRISPR / Cas9 in Xenopus laevis to disrupt recql4, a replication initiation factor. In humans, mutations in RECQL4 cause syndromes of reduced growth and skeletal abnormalities, with some overlap with Meier-Gorlin syndrome.

Collaborators

Dr Caroline Beck Department of Zoology, University of Otago

Professor Andrew Jackson University of Edinburgh, UK

Professor Grant Stewart University of Birmingham, UK

Professor Wojciech Niedzwiedz Institute of Cancer Research, London, UK

Dr Ernie Bongers Radboud University Nijmegen Medical Centre, the Netherlands

Alumni

Rebecca Dawson - BSc(Hons) Genetics (1st Class) 2016. Winner of 2016 DSM Poster Evening Honours Student Prize. Now undertaking a PhD at Victoria University, Wellington.

Isabella Thompson - PGDipSci Genetics (Distinction) 2017. Now undertaking Secondary School Teacher Training at Victoria University, Wellington.

Study forms

PDF packs containing information sheets, consent forms, clinical data forms, and sample sending instructions are available below.

New Zealand patient—molecular diagnosis unknown (PDF 2 MB)

New Zealand patient—molecular diagnosis known (PDF 2.9 MB)

Overseas patient—molecular diagnosis unknown (PDF 3 MB)

Overseas patient—molecular diagnosis known (PDF 1.6 MB)

Meier-Gorlin syndrome - clinical questionnaire for genotype-phenotype studies .docx 15 KB)

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Publications

Reynolds, J. J., Bicknell, L. S., Carroll, P., Higgs, M. R., Shaheen, R., Murray, J. E., … Stuart, G. S. (2017). Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nature Genetics, 49(4), 537-549. doi: 10.1038/ng.3790

Fenwick, A. L., Kliszczak, M., Cooper, F., Murray, J., Sanchez-Pulido, L., Twigg, S. R. F., … Bicknell, L. S. (2016). Mutations in CDC45, encoding an essential component of the pre-initiation complex, cause Meier-Gorlin syndrome and craniosynostosis. American Journal of Human Genetics, 99(1), 125-138. doi: 10.1016/j.ajhg.2016.05.019

Murray, J. E., van der Burg, M., IJspeert, H., Carroll, P., Wu, Q., Ochi, T., … Bicknell, L. S. (2015). Mutations in the NHEJ component XRCC4 cause primordial dwarfism. American Journal of Human Genetics, 96(3), 412-424. doi: 10.1016/j.ajhg.2015.01.013

Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., … Knoblich, J. A. (2013). Cerebral organoids model human brain development and microcephaly. Nature, 501(7467), 373-379. doi: 10.1038/nature12517

Bicknell, L. S., Walker, S., Klingseisen, A., Stiff, T., Leitch, A., Kerzendorfer, C., … Jeggo, P. A. (2011). Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nature Genetics, 43(4), 350-356. doi: 10.1038/ng.776

Journal - Research Article

Reynolds, J. J., Bicknell, L. S., Carroll, P., Higgs, M. R., Shaheen, R., Murray, J. E., … Stuart, G. S. (2017). Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nature Genetics, 49(4), 537-549. doi: 10.1038/ng.3790

Fenwick, A. L., Kliszczak, M., Cooper, F., Murray, J., Sanchez-Pulido, L., Twigg, S. R. F., … Bicknell, L. S. (2016). Mutations in CDC45, encoding an essential component of the pre-initiation complex, cause Meier-Gorlin syndrome and craniosynostosis. American Journal of Human Genetics, 99(1), 125-138. doi: 10.1016/j.ajhg.2016.05.019

Murray, J. E., van der Burg, M., IJspeert, H., Carroll, P., Wu, Q., Ochi, T., … Bicknell, L. S. (2015). Mutations in the NHEJ component XRCC4 cause primordial dwarfism. American Journal of Human Genetics, 96(3), 412-424. doi: 10.1016/j.ajhg.2015.01.013

Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., … Knoblich, J. A. (2013). Cerebral organoids model human brain development and microcephaly. Nature, 501(7467), 373-379. doi: 10.1038/nature12517

Bicknell, L. S., Bongers, E. M. H. F., Leitch, A., Brown, S., Schoots, J., Harley, M. E., … Jackson, A. P. (2011). Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nature Genetics, 43(4), 356-360. doi: 10.1038/ng.775

Bicknell, L. S., Walker, S., Klingseisen, A., Stiff, T., Leitch, A., Kerzendorfer, C., … Jeggo, P. A. (2011). Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nature Genetics, 43(4), 350-356. doi: 10.1038/ng.776

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