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@hgu.mrc.ac.uk
Telephone: +44 (0)131 332 2471
Fax: +44 (0)131 467 8456
Address: Medical Research Council
Human Genetics Unit
Western General Hospital
Crewe Road
Edinburgh EH4 2XU
Research Programme: Disorders of the Human Brain: Genetics and Function

 

Research Areas

My programme of work involves the identification novel genes for neurological disorders and then subsequently studying the function of the proteins they encode utilising cell biology and model organisms. My objectives are to gain novel insights into basic biological mechanisms and disease pathogenesis.

Autoimmune Disorders of the Brain

Aicardi-Goutieres syndrome (AGS) is a childhood-onset auto-inflammatory disorder of the brain that mimics congenital viral infection.  It also has clinical and immunological similarities with common autoimmune diseases such as SLE.  We have identified four genes for this autosomal recessive disorder that encode two nucleases, RibonucleaseH2 and TREX1. With this now defined molecular basis, AGS provides an important human model for nucleic-acid mediated inflammation.  Our aim is to study the cellular biology of Ribonuclease H2, defining the nucleic acids that accumulate as the consequence of its dysfunction and establish in vitro and in vivo how these nucleic acids stimulate an autoimmune response.

Disorders of Brain Size

Primary microcephaly and Seckel syndrome are disorders of markedly reduced brain size, with brain volumes similar to those of early hominids.  Recently, with our collaborators Penny Jeggo and Mark O’Driscoll, we have identified mutations in Pericentrin, a gene encoding a structural centrosomal protein, in Seckel syndrome patients. Surprisingly, we also established that it is a component of the ATR-dependant damage response pathway. This suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function, may act in  common developmental pathways determining human brain size.  We are currently working to identify further genes for microcephalic dwarfism with the intention of identifying other novel components of the ATR pathway.


Key/Selected Publications

 

  • 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

  • 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
  • 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
  • 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
  • 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
  • Rigby, R.E.; Leitch, A., and Jackson, A.P. Nucleic acid-mediated inflammatory diseases. BioEssays 30(9):833-842, 2008 PubMed Abstract