Dr Ian Jackson: Medical and Developmental Genetics

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Genetic Models for Human Disease

 

Summary

Genome sequencing has revealed that the entire gene complement of the human genome appears to be surprisingly small. Nevertheless, there are still more than 30,000 genes, the vast majority of which do not have a function ascribed to them. The mouse genome has virtually the same gene content as the human genome, and these are found in the same order as in humans over quite large distances. The mouse genome is an excellent model for the human genome, and mouse genetics offers an opportunity to elucidate gene function by studying mutations in those genes.

 

 

 

Publications

  1. Gautier, P.; Naranjo-Golborne, C.; Taylor, M.S.; Jackson, I.J. and Smyth, I. Expression of the fras1/frem gene family during zebrafish development and fin morphogenesis.
    Dev Dyn     237(11):3295-3304, 2008
    PubMed Abstract
  2. Webb, T.R.; Cross, S.H.; McKie, L.; Edgar, R.; Vizor, L.; Harrison, J.; Peters, J. and Jackson, I.J. Diphthamide modification of eEF2 requires a J-domain protein and is essential for normal development.
    J Cell Sci 121(Pt 19):3140-3145, 2008
    PubMed Abstract
  3. Hart, A.W.; Morgan, J.E.; Schneider, J.; West, K.; McKie, L.; Bhattacharya, S.; Jackson, I.J. and Cross, S.H. Cardiac malformations and midline skeletal defects in mice lacking filamin A. Hum Mol Genet 15(16):2457-2467, 2006
    PubMed Abstract
  4. Smyth, I.M.,.....58 additional authors.....Jackson, I.J. Genomic anatomy of the Tyrp1 (brown) deletion complex. PNAS 103(10):3704-3709, 2006 PubMed Abstract
  5. Wells, D.J.; Playle, L.C.; Enser, W.E.; Flecknell, P.A.; Gardiner, M.A.; Holland, J.; Howard, B.R.; Hubrecht, R.; Humphreys, K.R.; Jackson, I.J.; Lane, N.; Maconochie, M.; Mason, G.; Morton, D.B.; Raymond, R.; Robinson, V.; Smith, J.A. and Watt, N. Assessing the welfare of genetically altered mice. Lab Anim 40(2):111-114, 2006 PubMed Abstract
  6. Hart, A.; W, McKie, L.; Morgan, J.E.; Gautier, P.; West, K.; Jackson, I.J. and Cross, S.H. Genotype-phenotype correlation for mouse Pde6b mutations. Investigative Ophthalmology and Visual Science 46(9):3443-3450, 2005
    PubMed Abstract
  7. Jadeja, S.; Smyth, I.; Pitera, J.E.; Taylor, M.S.; van Haelst, M.; Bentley, E.; McGregor, L.; Hopkins, J.; Chalepakis, G.; Philip, N.; Aytes, A.P.; Watt, F.M.; Darling, S.M.; Jackson, I.; Woolf, A.S. and Scambler, P.J. Identifiacation of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs. Nature Genetics 37(5):520-525, 2005
    PubMed Abstract
  8. Van Agtmael, T.; Schlötzer-Schrehardt, U.; McKie, L.; Brownstein, D.G.; Lee, A.W.; Cross, S.H. ; Sado, Y.; Mullins, J.J.; Pöshl, E. and Jackson, I.J. Dominant mutations of Col4a1 result in basement membrane defects which lead to anterior segment defects and glomerupathy Human Molecular Genetics 14(21):3161-3168, 2005
    PubMed Abstract
  9. Cross, S.H.;,Morgan, J.E.; Pattyn, A.;West, K.; cKie, L.; lan Hart, A.; Thaung, C.; Brunet, J-F. and Jackson, I.J. Haploinsufficiency for Phox2b in mice causes dilated pupils and atrophy of the ciliary ganglion: mechanistic insights into human congenital central hypoventilation syndrome Human Molecular Genetics 13(14):1433-1439, 2004
    PubMed Abstract
  10. Lee, D.; Cross, S.H.; Strunk, K.E.; Morgan, J.E.; Bailey, D.M.; Jackson, I.J. and Threadgill, D.W. Wa5 is a novel ENU-induced antimorphic allele of the epidermal growth factor receptor.
    Mammalian Genome 15:525-536, 2004
    PubMed Abstract
  11. Smyth, I.; Du, X.; Taylor, M.S.; Justice, M.J.; Beutler, B. and Jackson, I.J. The extracellular matrix gene Frem 1 is essential for the normal adhesion of the embryonic epidermis. PNAS 101(37):13560-13565, 2004
    PubMed Abstract
  12. Unravelling What Makes Mammals Tick An article in The Scotsman newspaper
  13. Dukes-McEwan, J. and Jackson, I.J. The promises and problems of linkage analysis by using the current canine genome map. Mammalian Genome 13(11):667-672, 2002 PubMed Abstract
  14. Mouse Genome Sequencing Consortium Initial Sequencing and comparative analysis of the mouse genome.
    Nature     420:520-562, 2002
    PubMed Abstract
  15. The FANTOM Consortium and the RIKEN Genome Exploration Research Group Phase I & II Team Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs Nature 420 563-573, 2002
    PubMed Abstract
  16. Thaung, C.; Arnold, K.; Jackson, I.J. and Coffey, P.J. Presence of visual head tracking differentiates normal sighted from retinal degenerate mice.
    Neurosci Lett     325(1):21-24, 2002
    PubMed Abstract
  17. Thaung, C.; West, K.; Clark, B.J.; Morgan, J.E.; Arnold, K.; McKie, L.; Nolan, P.N.; Peters, J.; Hunter, A.J.; Brown, S.D.M.; Jackson, I.J. and Cross, S.H. Novel ENU-induced eye mutations in the mouse – models for human eye disease Human Molecular Genetics 11(7):755-767, 2002 PubMed Abstract
  18. Jackson, I.J. Mouse mutagenesis on target. Nature Genetics 28:198-200, 2001
    PubMed Abstract
  19. Jackson, I.J. Mouse Genetics: Making Sense of the Sequence.
    Current Biology     11(8):R311-R314, 2001
    PubMed Abstract
  20. Simpson, E.H.; Suffolk, R.; Bell, J.A.; Jordan, S.A.; Johnson, D.K.; Hunsicker, P.R.; Weber, J.S.; Justice.M.J. and Jackson, I.J. A comparative transcript map and candidates for mutant phenotypes in the Tyrp1 (brown) deletion complex homologous to human 9p21-23.
    Mammalian Genome 11:58-63, 2000
    PubMed Abstract

Collaborators outwith the Unit

  • Professor Steve Brown MRC Mammalian Genetics Unit
  • Dr Jo Peters MRC Mammalian Genetics Unit
  • Dr Ian Smyth Monash University
  • Dr Monica Justice Baylor College of Medicine
  • Dr Simon John The Jackson Laboratory


 

Lab Members

Current lab members involved in this work are:

 

 

  1. Molecular Genetics and Development of Melanocytes
  2. Genetic Models of Human Disease
    (this page)

 

In addition these mutant animals are models for human diseases and help dissect the disease processes. Numerous centres throughout the world are generating random mutations by chemical treatment and we are collaborating with two of them to discover genes involved involved in eye development and function, and to produce a detailed picture of gene function in discrete regions of the genome.

 

Purpose

A full understanding of human gene function in normal biology and in disease requires the study of gene mutations. We use mouse mutations to gain a fuller understanding of gene function, and to study genetic models of human disease.

 

Approach, Progress and Future Work

We have collaborated with the MRC Mammalian Genetics Unit at Harwell to screen offspring of mice mutagenised with ethyl nitrosourea (ENU) for eye defects

 

MRC Harwell Mutagenesis Mutabase We developed a rapid screen for mouse visual function (Thaung et al 2002a), and we screened several thousand mice. We also carried out physical eye examinations with slit lamp and indirect ophthalmoscopy on over six thousand mice (Thaung et al 2002b). We have identified about 25 mutations that affect eye development and in almost all have identified the gene affected and found the base change produced by the ENU treatment. These include seven novel mutant alleles of Pde6b, the retinal specific phosphodiesterase (Hart et al 2005), four new alleles of the paired box gene, Pax6, two new alleles of the transcription factor gene Mitf, two novel mutations of the Col4a1 gene (van Agtmael et al 2005)and mutations in the EGF receptor gene Egfr (Lee et al 2004) and the homeobox gene Phox2b (Cross et al 2004). Methods we developed for phenotyping mouse eye and vision mutants are found at the European Mouse Phenotyping Resource of Standardised Screens (EMPReSS) website.

 

We are now generating recessive mutations affecting eyes and vision using a 3-generation screen, again in collaboration with MGU at Harwell.

 

retina

Left: normal retina Right: retina of mouse with a loss-of-function mutation in Pde6b

 

mouse heterozygousLeft: mouse heterozygous for a dominant-negative mutation of Mitf Right: mouse homozygous for the same mutation

 

For many years we have studied a region on mouse chromosome 4, encompassing the Tyrp1 gene (Simpson et al 2000). This has been a target for mutagenesis, in particular using various types of radiation at Oak Ridge National Labs, USA. As a consequence there is a collection of over 25 deletions of various sizes which remove different amounts of surrounding DNA, and neighbouring genes. In collaboration with Monica Justice at Baylor College of Medicine, Houston, Texas we are identifying ENU-induced mutations that map within these deletions. In order to facilitate gene identification the UK Mouse Genome Sequencing Consortium, of which we are a part, has generated finished and hand annotated sequence for the 22Mb interval covering all the deletions (Smyth et al 2006).

 

We have already identifed in the region a gene, Frem1, which is mutated in the classical head-blebs mutation, and in 2 ENU-induced alleles (Smyth et al 2004). This is a model for human Fraser's Syndrome. We also showed, in collaboration with Pete Scambler, that a related gene, Frem2 is affected in the mouse eye-blebs mutant, and in human Fraser's patients (Jaedeja et al 2005).

 

Another mutation in the chromosome 4 region, depilated, caused hair loss and we are studying a candidate gene that underlies the phenotype.

 

We are also carried out a screen for ENU mutations that map within a ~3Mb deletion on mouse chromosome 2, that includes the Pax6 gene. The UK Mouse Genome Sequencing Consortium has also sequenced this region to enable gene identification and mutation detection. We have identified a lethal mutation in the region and found the affected gene.