Congenital Nystagmus

							Congenital Nystagmus



           Erik Twaroski
                    Eye gifs from <http://www.omlab.org>
Characteristics
 Uncontrolled   oscillation of the eyes



  Onset at birth or within several
  months
 1 in 1,500 live births
Patterns of inheritance
 autosomal dominant
 autosomal recessive
 X-linked dominant
 X-linked recessive
 X-linked dominant with incomplete
  penetrance
Genes involved
 PAX6
 NYS1
PAX6
   Highly conserved sequence
       All known mutations involve a single change in
        the amino acid sequence
   Positional cloning to determine area of
    genome (Hanson et al.)
       Maps to 11p13
   Haploinsufficiency consistently present
    with all disorders associated with PAX6
       Mutation in both copies is lethal
   Thought to be the primary gene until
    recently
PAX6 (cont.)




 Exons 4-13 contain coding regions. DNA binding
              domains and a linker.
PAX6 mutations




 Sequence differences between normal and CN.
   Mutation creates a BsrI restriction site.
Picture from Hanson et al.
Mutation causing CN (Gly  Val) shown in
    yellow at the N-terminal domain
PAX6 (cont.)
   Complete loss of PAX6 in mice is lethal
       Knockouts cannot be made
   Elimination of one copy results is a small
    eye phenotype




            Picture from <http://www.mouse-genome.bcm.tmc.edu/ENU/publicimageview.asp>
Another gene?
 Until1999 PAX6 was believed to be the
  only gene responsible for CN
      mutations resulted in eye disorders
   All

   CN could only be linked to PAX6
NYS1
 Cabotet al. first to report mapping
 CN to X chromosome
   Xp11.4-11.3

   Dominant   with incomplete penetrance
 Important for eye development
 Majority of research done on this
  gene
Picture from Cabot et al.
NYS1 (cont.)
 Started   by finding microsatellites on
 Xp
   Sequences   known from the Genome
    Database
   Regions of CA repeats

 Recombinationevents indicated which
 markers were closely linked
Recombination events in parents of affected individuals




                                          Picture from Cabot et al.
LOD scores for loci around NYS1
Picture from Cabot et al.
                    More statistical analysis




Support for location of an X-linked ICN gene, with respect to three chromosome
Xp markers. Likelihood estimates are given in log10. Distances between marker loci,
in centimorgans, are shown along the X-axis. The maximum location score for NYS1
is between DXS8015 and DXS1003, over the locus DXS993.

                                                                           Picture from Cabot et al.
Map of Xp
            Based on this NYS1 is
            between DXS8015 and
             DXS1003 (18.6-cM)
  X-inactivation pattern between normal
           and carrier/affected




Skewed X-inactivation patterns in affected
   haplotype or unaffected haplotype
Treatments
 Currently  no treatments available
 CN does not appear to interfere with
  visual function.
 Dell’Osso and Jacobs characterized
  the ocular oscillations of CN over a
  35 year study published in July 2004
Treatments (cont.)
 Dell’Ossoand Jacobs found that the
 body is able to compensate
   Eventhe most severe cases showed signs
   of some compensation
 More  research needs to be conducted
 to further understand how the body
 is able to compensate
Questions?
References
1.   Annick Cabet, Jean-Michel Rozet, Sylvie Gerber, Isabelle Perrault,
     Dominique Ducroq, Asmae Smahi, Eric Souied, Arnold Munnich, and
     Josseline Kaplan. “A Gene for X-Linked Idiopathic Congenital Nystagmus
     (NYS1) Maps to Chromosome Xp11.4-p11.3.” American Journal of Human
     Genetics 64:1141-1146, 1999.

2.   Isabel Hanson, Amanda Churchill, James Love, Richard Axton, Tony Moore,
     Michael Clarke, Francoise Meire, and Veronica van Heyningen. “Missense
     mutations in the most ancient residues of the PAX6 paired domain underlie a
     spectrum of human congenital eye malformations.” Human Molecular
     Genetics, 1999, Vol. 8, No. 2.

3.   Jonathan B. Jacobs and Louis F. Dell’Osso. “Congenital nystagmus:
     Hypotheses for its genesis and complex waveforms within a behavioral ocular
     motor system model.” Journal of Vision 4: 604-625, 2004.

4.   Sanjaya Singh, Lian Y. Chao, Rajnikant Mishra, Jonathan Davies, and Grady
     F. Saunders. “Missense mutation at the C-terminus of PAX6 negatively
     modulates homeodomain function.” Human Molecular Genetics, 2001, Vol.
     10, No. 9.