Transcript 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


Positional cloning to determine area of
genome (Hanson et al.)


Maps to 11p13
Haploinsufficiency consistently present
with all disorders associated with PAX6


All known mutations involve a single change in
the amino acid sequence
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?
 Until
1999 PAX6 was believed to be the
only gene responsible for CN
 All
mutations resulted in eye disorders
 CN could only be linked to PAX6
NYS1
 Cabot
et al. first to report mapping
CN to X chromosome
 Xp11.4-11.3
 Dominant
 Important
with incomplete penetrance
for eye development
 Majority of research done on this
gene
Picture from Cabot et al.
NYS1 (cont.)
 Started
Xp
by finding microsatellites on
 Sequences
known from the Genome
Database
 Regions of CA repeats
 Recombination
events 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’Osso
and Jacobs found that the
body is able to compensate
 Even
the 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.