Professor Veronica van Heyningen: Medical and Developmental Genetics

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Genes, Environment and Evolution in Eye Development
and Malformations: PAX6, SOX2, OTX2


 

  1. Fantes, J.; Ragge, N.K.; Lynch, S.A.; McGill, N.I.; Collin, J.R.; Howard-Peebles, P.N.; Hayward, C.; Vivian, A.J.; Williamson, K.; van Heyningen, V. and Fitzpatrick, D.R. Mutations in SOX2 cause anophthalmia.
    Nat Genet     33(4):461-463, 2003
    PubMed Abstract
  2. Mitchell, T.N.; Free, S.L.; Williamson, K.A.; Stevens, J.M.; Churchill, A.J.; Hanson, I.M.; Shorvon, S.D.; Moore, A.T.; van Heyningen, V. and Sisodiya, S.M. Polymicrogyria and absence of pineal gland due to PAX6 mutation.
    Ann Neurol 53(5):658-663, 2003
    PubMed Abstract
  3. Crolla, J.A. and van Heyningen, V. Frequent chromosome aberrations revealed by molecular cytogenetic studies in patients with aniridia.
    Am J Hum Genet 71(5): 1138-1149, 2002
    PubMed Abstract
  4. Estivill-Torrus, G.; Pearson, H.; van Heyningen, V.; Price, D.J. and Rashbass, P. Pax6 is required to regulate the cell cycle and the rate of progression from symmetrical to asymmetrical division in mammalian cortical progenitors. Development 129(2):455-466, 2002 PubMed Abstract
  5. Griffin, C.; Kleinjan, D.A.; Doe, B., andvan Heyningen, V. New 3' elements control Pax6 expression in the developing pretectum, neural retina and olfactory region. Mech Dev 112(1-2):89-100, 2002 PubMed Abstract
  6. Jamieson, R.V.; Perveen, R.; Kerr, B.; Carette, M.; Yardley, J.; Heon, E.; Wirth, M.G.; Heyningen, V.; Donnai, D.; Munier, F. and Black, G.C. Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma. Hum Mol Genet 11(1): 33-42, 2002
    PubMed Abstract
  7. Kleinjan, D.A.; Seawright, A.; Elgar, G., and van Heyningen, V. Characterization of a novel gene adjacent to PAX6, revealing synteny conservation with functional significance.
    Mamm Genome     13(2): 102-107, 2002
    PubMed Abstract
  8. Morrison, D.; Fitzpatrick, D.; Hanson, I.; Williamson, K.; Heyningen, V.; Fleck, B.; Jones, I.; Chalmers, J. and Campbell, H. National study of microphthalmia, anophthalmia, and coloboma (MAC) in Scotland: investigation of genetic aetiology. J Med Genet 39(1):16-22, 2002 PubMed Abstract
  9. van Heyningen, V. and Williamson, K.A. PAX6 in sensory development.
    Hum Mol Genet 11(10): 1161-1167, 2002 PubMed Abstract
  10. Kleinjan, D.A.; Seawright, A.; Schedl, A.; Quinlan, R.A.; Danes, S. and Heyningen, V. Aniridia-associated translocations, DNase hypersensitivity, sequence comparison and transgenic analysis redefine the functional domain of PAX6. Hum Mol Genet 10(19):2049-2059, 2001 PubMed Abstract
  11. Sisodiya, S.M.; Free, S.L.; Williamson, K.A.; Mitchell, T.N.; Willis, C.; Stevens, J.M.; Kendall, B.E.; Shorvon, S.D.; Hanson, I.M.; Moore, A.T. and van Heyningen, V. PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans. Nat Genet 28(3):214-216, 2001 
    PubMed Abstract
  12. Engelkamp, D.; Rashbass, P.; Seawright, A. and van Heyningen, V. Role of Pax6 in development of the cerebellar system. Development 126(16):3585-3596, 1999 PubMed Abstract
  13. Hanson, I.; Churchill, A.; Love, J.; Axton, R.; Moore, T.; Clarke, M.; Meire, F. and van Heyningen, V. Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations.
    Hum Mol Genet     8(2): 165-172, 1999
    PubMed Abstract
  14. Kleinjan, D.J. and van Heyningen, V. Position effect in human genetic disease. Hum Mol Genet 7(10):1611-1618, 1998 PubMed Abstract
  15. Miles, C.; Elgar, G.; Coles, E.; Kleinjan, D.J.; van Heyningen, V. and Hastie, N. Complete sequencing of the Fugu WAGR region from WT1 to PAX6: dramatic compaction and conservation of synteny with human chromosome 11p13. Proc Natl.Acad Sci 95(22):13068-13072, 1998 PubMed Abstract
  16. Prosser, J. and van Heyningen, V. PAX6 mutations reviewed.
    Hum Mutat 11(2):93-108, 1998
    PubMed Abstract
  17. Ericson, J.; Rashbass, P.; Schedl, A.; Brenner-Morton, S.; Kawakami, A.; van Heyningen, V. ; Jessell, T.M. and Briscoe, J. Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling. Cell 90(1):169-180, 1997
    PubMed Abstract
  18. Schedl, A.; Ross, A.; Lee, M.; Engelkamp, D.; Rashbass, P.; van Heyningen, V. and Hastie, N.D. Influence of PAX6 gene dosage on development: overexpression causes severe eye abnormalities.
    Cell     86(1):71-82, 1996
    PubMed Abstract
  19. Fantes, J.; Redeker, B.; Breen, M.; Boyle, S.; Brown, J.; Fletcher, J.; Jones, S.; Bickmore, W.; Fukushima, Y.; Mannens, M.; Danes, S.; van Heyningen, V. and Hanson, I.M. Aniridia-associated cytogenetic rearrangements suggest that a position effect may cause the mutant phenotype. Human Molecular Genetics 4:415-422 1995
    PubMed Abstract
  20. Hanson, I. and van Heyningen, V. Pax6: more than meets the eye.
    Trends Genet     11(7): 268-272, 1995
    PubMed Abstract
  21. Hanson, I.M.; Fletcher, J.M.; Jordan, T.; Brown, A.; Taylor, D.; Adams, R.J.; Punnett, H.H. and van Heyningen, V. Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly. Nat Genet 6(2):168-173, 1994
    PubMed Abstract
  22. Hanson, I.M.; Seawright, A.; Hardman, K.; Hodgson, S.; Zaletayev, D.; Fekete, G., and van Heyningen, V. PAX6 mutations in aniridia.
    Hum Mol Genet     2(7):915-920, 1993
    PubMed Abstract
  23. Jordan, T.; Hanson, I.; Zaletayev, D.; Hodgson, S.; Prosser, J.; Seawright, A.; Hastie, N., and van Heyningen, V. The human PAX6 gene is mutated in two patients with aniridia.
    Nat Genet     1(5):328-332, 1992
    PubMed Abstract
  24. Hill, R.E.; Favor, J.; Hogan, B.L.; Ton, C.C.; Saunders, G.F.; Hanson, I.M.; Prosser, J.; Jordan, T.; Hastie, N.D. and van Heyningen, V. Mouse small eye results from mutations in a paired-like homeobox-containing gene.
    Nature     354(6354):522-525, 1991
    PubMed Abstract
  25. Ton, C.C.; Hirvonen, H.; Miwa, H.; Weil, M.M.; Monaghan, P.; Jordan, T.; van Heyningen, V.; Hastie, N.D.; Meijers-Heijboer, H.; Drechsler, M. and . Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region.
    Cell     67(6):1059-1074, 1991
    PubMed Abstract
  1. Genetics of developmental eye malformations
  2. How gene expression is regulated
  3. How stress response pathways modulate the effect of mutations

 

 

Key Publications

  1. Hingorani, M.; Williamson, K.A.; Moore, A.T. and van Heyningen, V. Detailed ophthalmological evaluation of 43 individuals with PAX6 mutations. Invest Ophthalmol Vis Sci 50(6):2581-90, 2009 PubMed Abstract
  2. Kleinjan, D.A.; Bancewicz, R.M.; Gautier, P.; Dahm, R.; Schonthaler, H.B.; Damante, G.; Seawright, A.; Hever, A.M.; Yeyati, P.L.; van Heyningen, V. and Coutinho, P. Subfunctionalization of duplicated zebrafish pax6 genes by cis-regulatory divergence. PLoS Genet 4(2):e29, 2008
    PubMed Abstract
  3. Robinson, D.O.; Howarth, R.J.; Williamson, K.A.; van Heyningen, V.; Beal, S.J. and Crolla, J.A. Genetic analysis of chromosome 11p13 and the PAX6 gene in a series of 125 cases referred with aniridia.
    Am J Med Genet A     146A(5): 558-569, 2008 PubMed Abstract
  4. Yeyati, P.L. and van Heyningen, V. Incapacitating the evolutionary capacitor: Hsp90 modulation of disease.
    Curr Opin Genet Dev     18(3):264-272, 2008 PubMed Abstract
  5. Bamiou, D.E.; Free, S.L.; Sisodiya, S.M.; Chong, W.K.; Musiek, F.; Williamson, K.A.; van Heyningen, V.; Moore, A.T.; Gadian, D. and Luxon, L.M. Auditory interhemispheric transfer deficits, hearing difficulties, and brain magnetic resonance imaging abnormalities in children with congenital aniridia due to PAX6 mutations. Arch Pediatr Adolesc Med 161(5):463-469, 2007
    PubMed Abstract
  6. Henderson, R.A.; Williamson, K.; Cumming, S.; Clarke, M.P.; Lynch, S.A.; Hanson, I.M.; Fitzpatrick, D.R.; Sisodiya, S. and van Heyningen, V. Inherited PAX6, NF1 and OTX2 mutations in a child with microphthalmia and aniridia.
    Eur J Hum Genet 15(8):898-901, 2007 PubMed Abstract
  7. Hewitt, A.W.; Kearns, L.S.; Jamieson, R.V.; Williamson, K.A.; van Heyningen, V. and Mackey, D.A. PAX6 mutations may be associated with high myopia.
    Ophthalmic Genet     28(3):179-182, 2007 PubMed Abstract
  8. Manuel, M.; Georgala, P.A.; Carr, C.B.; Chanas, S.; Kleinjan, D.A.; Martynoga, B.; Mason, J.O.; Molinek, M.; Pinson, J.; Pratt, T.; Quinn, J.C.; Simpson, T.I.; Tyas, D.A.; van Heyningen, V.; West, J.D. and Price, D.J. Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical progenitor proliferation with little effect on cortical arealization. Development 134(3):545-555, 2007 PubMed Abstract
  9. van Heyningen, V.; Hoovers, J.M.; de Kraker, J. and Crolla, J.A. Raised risk of Wilms tumour in patients with aniridia and submicroscopic WT1 deletion.
    J Med Genet     44(12):87-790, 2007
    PubMed Abstract
  10. Yeyati, P.L.; Bancewicz, R.M.; Maule, J. and van Heyningen, V. Hsp90 selectively modulates phenotype in vertebrate development. PLoS Genet 3(3):e43, 2007
    PubMed Abstract
  11. Faivre, L.; Williamson, K.A.; Faber, V.; Laurent, N.; Grimaldi, M.; Thauvin-Robinet, C.; Durand, C.; Mugneret, F.; Gouyon, J.B.; Bron, A.; Huet, F.; Hayward, C.; van Heyningen, V. and FitzPatrick, D.R. Recurrence of SOX2 anophthalmia syndrome with gonosomal mosaicism in a phenotypically normal mother.
    Am J Med Genet A. 140A: 636-639, 2006
    PubMed Abstract
  12. Hever, A.M.; Williamson, K.A. and van Heyningen, V. Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2.
    Clin Genet 69(6):459-470, 2006
    PubMed Abstract
  13. Kleinjan, D.A.; Seawright, A.; Mella, S.; Carr, C.B.; Tyas, D.A.; Simpson, T.I.; Mason, J.O.; Price, D.J. and van Heyningen, V. Long-range downstream enhancers are essential for Pax6 expression. Dev Biol 299(2):563-581, 2006 PubMed Abstract
  14. Sisodiya, S.M.; Ragge, N.K.; Cavalleri, G.L.; Hever, A.; Lorenz, B.; Schneider, A.; Williamson, K.A.; Stevens, J.M.; Free, S.L.; Thompson, P.J.; van Heyningen, V. and Fitzpatrick, D.R. Role of SOX2 mutations in human hippocampal malformations and epilepsy. Epilepsia 47(3):534-542, 2006 PubMed Abstract
  15. Williamson, K.A.; Hever, A.M.; Rainger, J.; Rogers, R.C.; Magee, A.; Fiedler, Z.; Keng, W.T.; Sharkey, F.H.; McGill, N.; Hill, C.J.; Schneider, A.; Messina, M.; Turnpenny, P.D.; Fantes, J.A.; van Heyningen, V. and Fitzpatrick, D.R. Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum Mol Genet 15(9):1413-1422, 2006
    PubMed Abstract
  16. Kleinjan, D.A. and van Heyningen, V. Long-range control of gene expression: emerging mechanisms and disruption in disease. Am J Hum Genet 76(1):8-32, 2005 PubMed Abstract
  17. Ragge, N.K.; Brown, A.G.; Poloschek, C.M.; Lorenz, B.; Henderson, R.A.; Clarke, M.P.; Russell-Eggitt, I.; Fielder, A.; Gerrelli, D.; Martinez-Barbera, J.P.; Ruddle, P.; Hurst, J.; Collin, J.R.; Salt, A.; Cooper, S.T.; Thompson, P.J.; Sisodiya, S.M.; Williamson, K.A.; Fitzpatrick, D.R.;
    van Heyningen, V. and Hanson, I.M. Heterozygous mutations of OTX2 cause severe ocular malformations. Am J Hum Genet 76(6):1008-1022, 2005
    PubMed Abstract
  18. Ragge, N.K.; Lorenz, B.; Schneider, A.; Bushby, K.; de Sanctis, L.; de Sanctis, U.; Salt, A.; Collin, J.R.; Vivian, A.J.; Free, S.L.; Thompson, P.; Williamson, K.A.; Sisodiya, S.M.; van Heyningen, V. and Fitzpatrick, D.R. SOX2 anophthalmia syndrome.
    Am J Med Genet A     135(1):1-7, 2005
    PubMed Abstract
  19. Bamiou, D.E.; Musiek, F.E.; Sisodiya, S.M.; Free, S.L.; Davies, R.A.; Moore, A.; van Heyningen, V. and Luxon, L.M. Deficient auditory interhemispheric transfer in patients with PAX6 mutations.
    Ann Neurol     56(4):503-509, 2004
    PubMed Abstract
  20. Kleinjan, D.A.; Seawright, A.; Childs, A.J., and van Heyningen, V. Conserved elements in Pax6 intron 7 involved in (auto)regulation and alternative transcription.
    Dev Biol     265(2):462-477, 2004
    PubMed Abstract
  21. van Heyningen, V. and Yeyati, P.L. Mechanisms of non-Mendelian inheritance in genetic disease.
    Hum Mol Genet 13::R225-R233, 2004
    PubMed Abstract