Research Biographies

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DR ANDREW JACKSON

Medical and Developmental Genetics

Programme Leader

MRC Senior Clinical Fellow


Andrew Jackson

Contact Details

E-mail address: andrew.jackson@igmm.ed.ac.uk
Telephone: +44 (0)131 332 2471
Fax: +44 (0)131 467 8456
Address: MRC Human Genetics Unit MRC IGMM, University of Edinburgh Western General Hospital, Crewe Road, Edinburgh EH4 2XU
Research Programme: Genetic Disorders of Growth, Inflammation and the Brain

 

Research Areas

My research involves both the identification new genes for neurological disorders works and defining the functional role of the proteins they encode utilising cell biology and model organisms. I aim to place these genes into cellular pathways, provide novel insights into biological mechanisms and advance our understanding of disease processes.

Neuro-inflammation: Nucleases that mimic viral infection

Nucleic acids are potent activators of innate immunity. Innate immune sensing of nucleic acids provides resistance against viral infection and is important in the aetiology of autoimmune diseases.  Aicardi-Goutières syndrome (AGS) is an autoinflammatory disorder mimicking in utero viral infection of the brain and is inherited as an autosomal recessive trait. Phenotypically and immunologically it exhibits many similarities to Systemic Lupus Erythematosus (SLE). In recent years we have identified mutations for this disease in four genes that encode two nucleases. We hypothesise that in AGS and SLE, nucleic acid byproducts stimulate a chronic and inappropriate innate immune response. Given that AGS is a monogenic disorder with a defined molecular basis, we are using it as a model for common autoimmune disease to explore the cellular pathogenesis and molecular pathways implicated in nucleic acid triggered inflammatory responses. This should provide new insights into the aetiology of systemic autoimmune disease and immune-mediated damage of host by its inappropriate response to viral infection.


Growth and human brain size

The greatest difference between mammals is size, with a 75 million-fold difference between smallest and largest. In addition, a defining feature of humans is the large evolutionary expansion of the cerebral cortex. In marked contrast to the exquisite detail in which developmental patterning has been defined in model organisms, much remains to be learnt about the developmental and evolutionary factors controlling organ and organism size. Over the last few years we have identified seven microcephalic primordial dwarfism genes that regulate cerebral cortex volume and organism size, encoding fundamental components of cellular machinery controlling cell proliferation. We hypothesise that such genes are components of common cellular pathway(s) and that these human disorders can provide novel insights into developmental regulation of organism size. We are using genetic, cellular and developmental studies to address this hypothesis and further define the pathogenesis of these conditions.  This work should contribute to our understanding of vertebrate growth regulation and help us understand how the human brain evolved.

Key/Selected Publications

  • Bicknell, L.S.; Walker, S.; Klingseisen, A.; Stiff, T.; Leitch, A.; Kerzendorfer, C.; Martin, C.A.; Yeyati, P.; Al Sanna, N.; Bober, M.; Johnson, D.; Wise, C.; Jackson, A.P.; O'Driscoll, M. and Jeggo, P.A. Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nat.Genet 43(4):350-5, 2011
    PubMed Abstract
  • Bicknell, L.S.; Bongers, E.M.; Leitch, A.; Brown, S.; Schoots, J.; Harley, M.E.; Aftimos, S.; Al Aama, J.Y.; Bober, M.; Brown, P.A.; van Bokhoven, H.; Dean, J.; Edrees, A.Y.; Feingold, M.; Fryer, A.; Hoefsloot, L.H.; Kau, N.; Knoers, N.V.; Mackenzie, J.; Opitz, J.M.; Sarda, P.; Ross, A.; Temple, I.K.; Toutain, A.; Wise, C.A.; Wright, M. and Jackson, A.P. Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nat.Genet 43(4):356-9, 2011 PubMed Abstract
  • Griffith, E.; Walker, S.; Martin, C.A.; Vagnarelli, P.; Stiff, T.; Vernay, B.; Al Sanna, N.; Saggar, A.; Hamel, B.; Earnshaw, W.C.; Jeggo, P.A.; Jackson, A.P. and O'Driscoll, M. Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat Genet 40(2):232-236, 2008 PubMed Abstract
  • Brunk, K.; Vernay, B.; Griffith, E.; Reynolds, N.L.; Strutt, D.; Ingham, P.W. and Jackson, A.P. Microcephalin coordinates mitosis in the syncytial Drosophila embryo. Journal of Cell Science 120:3578-3588, 2007 PubMed Abstract
  • Alderton, G.K.; Galbiati, L.; Griffith, E.; Surinya, K.H.; Neitzel, H.; Jackson, A.P.; Jeggo, P.A. and O'Driscoll, M. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Nat Cell Biol 8(7):725-733, 2006 PubMed Abstract
  • Crow, Y.J.; Hayward, B.E.; Parmar, R.; Robins, P.; Leitch, A.; Ali, M.; Black, D.N.; van Bokhoven, H.; Brunner, H.G.; Hamel, B.C.; Corry, P.C.; Cowan, F.M.; Frints, S.G.; Klepper, J.; Livingston, J.H.; Lynch, S.A.; Massey, R.F.; Meritet, J.F.; Michaud, J.L.; Ponsot, G.; Voit, T.; Lebon, P.; Bonthron, D.T.; Jackson, A.P.; Barnes, D.E. and Lindahl, T. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nat Genet 38(8):917-920, 2006 PubMed Abstract
  • Crow, Y.J.; Leitch, A.; Hayward, B.E.; Garner, A.; Parmar, R.; Griffith, E.; Ali, M.; Semple, C.; Aicardi, J.; Babul-Hirji, R.; Baumann, C.; Baxter, P.; Bertini, E.; Chandler, K.E.; Chitayat, D.; Cau, D.; Dery, C.; Fazzi, E.; Goizet, C.; King, M.D.; Klepper, J.; Lacombe, D.; Lanzi, G.; Lyall, H.; Martinez-Frias, M.L.; Mathieu, M.; McKeown, C.; Monier, A.; Oade, Y.; Quarrell, O.W.; Rittey, C.D.; Rogers, R.C.; Sanchis, A.; Stephenson, J.B.; Tacke, U.; Till, M.; Tolmie, J.L.; Tomlin, P.; Voit, T.; Weschke, B.; Woods, C.G.; Lebon, P.; Bonthron, D.T.; Ponting, C.P. and Jackson, A.P. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nat Genet 38(8):910-916, 2006 PubMed Abstract


Recent Publications

  • Pagnamenta AT, Murray JE, Yoon G, Sadighi AE, Harrison V, Bicknell LS, Ajilogba K, Stewart H, Kini U, Taylor JC, Keays DA, Jackson AP, Knight SJ: A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss. Am J Med Genet A 158A:2577-2582, 2012.
    PubMed Abstract
  • Bober MB, Niiler T, Duker AL, Murray JE, Ketterer T, Harley ME, Alvi S, Flora C, Rustad C, Bongers EM, Bicknell LS, Wise C, Jackson AP: Growth in individuals with Majewski osteodysplastic primordial dwarfism type II caused by pericentrin mutations. Am J Med Genet A 158A:2719-2725, 2012.
    PubMed Abstract
  • Murray JE, Jackson AP: Exploring microcephaly and human brain evolution. Dev Med Child Neurol 54:580-581, 2012.
    PubMed Abstract
  • Reijns MA, Rabe B, Rigby RE, Mill P, Astell KR, Lettice LA, Boyle S, Leitch A, Keighren M, Kilanowski F, Devenney PS, Sexton D, Grimes G, Holt IJ, Hill RE, Taylor MS, Lawson KA, Dorin JR, Jackson AP: Enzymatic removal of ribonucleotides from DNA is essential for Mammalian genome integrity and development
    Cell 149:1008-1022, 2012.
    PubMed Abstract
  • de Munnik SA, Bicknell LS, Aftimos S, Al-Aama JY, van BY, Bober MB, Clayton-Smith J, Edrees AY, Feingold M, Fryer A, van Hagen JM, Hennekam RC, Jansweijer MC, Johnson D, Kant SG, Opitz JM, Ramadevi AR, Reardon W, Ross A, Sarda P, Schrander-Stumpel CT, Schoots J, Temple IK, Terhal PA, Toutain A, Wise CA, Wright M, Skidmore DL, Samuels ME, Hoefsloot LH, Knoers NV, Brunner HG, Jackson AP, Bongers EM: Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis
    Eur J Hum Genet 20:598-606, 2012.
    PubMed Abstract
  • Reijns MA, Bubeck D, Gibson LC, Graham SC, Baillie GS, Jones EY, Jackson AP: The structure of the human RNase H2 complex defines key interaction interfaces relevant to enzyme function and human disease. J Biol Chem 286:10530-10539, 2011 PubMed abstract
  • Leung JW, Leitch A, Wood JL, Shaw-Smith C, Metcalfe K, Bicknell LS, Jackson AP, Chen J: Set protein associates with microcephalin/MCPH1 and regulates chromosome condensation. J Biol Chem 286(24): 21393-400 2011. PubMed Abstract
  • Huang-Doran I, Bicknell LS, Finucane FM, Rocha N, Porter KM, Tung YC, Szekeres F, Krook A, Nolan JJ, O'Driscoll M, Bober M, O'Rahilly S, Jackson AP, Semple RK: Genetic defects in human pericentrin are associated with severe insulin resistance and diabetes. Diabetes 60:925-935, 2011.
    PubMed Abstract
  • Bubeck, D.; Reijns, M.A.; Graham, S.C.; Astell, K.R.; Jones, E.Y. and Jackson, A.P. PCNA directs type 2 RNase H activity on DNA replication and repair substrates. Nucleic Acids Res 39(9):3652-66, 2011
    PubMed Abstract
  • Jackson, A.P. Diversifying microtubules in brain development. Nat.Genet. 41(6):638-640, 2009 PubMed Abstract
  • Miller, T.D.; Jackson, A.P.; Barresi, R.; Smart, C.M.; Eugenicos, M.; Summers, D.; Clegg, S.; Straub, V. and Stone, J. Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD): clinical features including sphincter disturbance in a large pedigree.
    J Neurol Neurosurg Psychiatry 80(5):583-584, 2009 PubMed Abstract
  • Peng, G.; Yim, E.K.; Dai, H.; Jackson, A.P.; Burgt, I.; Pan, M.R.; Hu, R.; Li, K. and Lin, S.Y. BRIT1/MCPH1 links chromatin remodelling to DNA damage response. Nat.Cell Biol 11(7):865-872, 2009 PubMed Abstract
  • Sharkey, F.H.; Morrison, N.; Murray, R.; Iremonger, J.; Stephen, J.; Maher, E.; Tolmie, J. and Jackson, A.P. 17q21.31 microdeletion syndrome: further expanding the clinical phenotype. Cytogenet.Genome Res 127(1):61-66, 2009 PubMed Abstract