Congenital Nystagmus

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Congenital Nystagmus

• Erik Twaroski

Eye gifs from lthttp//www.omlab.orggt
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Characteristics

• Uncontrolled oscillation of the eyes
• Onset at birth or within several months
• 1 in 1,500 live births

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Patterns of inheritance

• autosomal dominant
• autosomal recessive
• X-linked dominant
• X-linked recessive
• X-linked dominant with incomplete penetrance

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Genes involved

• PAX6
• NYS1

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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

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PAX6 (cont.)
Exons 4-13 contain coding regions. DNA binding
domains and a linker.
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PAX6 mutations
Sequence differences between normal and CN.
Mutation creates a BsrI restriction site.
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Picture from Hanson et al.
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Mutation causing CN (Gly ? Val) shown in yellow
at the N-terminal domain
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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 lthttp//www.mouse-genome.bcm.tmc.edu
/ENU/publicimageview.aspgt
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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

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NYS1

• Cabot et 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

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Picture from Cabot et al.
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NYS1 (cont.)

• Started by finding microsatellites on Xp
• Sequences known from the Genome Database
• Regions of CA repeats
• Recombination events indicated which markers were
  closely linked

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Recombination events in parents of affected
individuals
Picture from Cabot et al.
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LOD scores for loci around NYS1
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Picture from Cabot et al.
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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.
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Map of Xp
Based on this NYS1 is between DXS8015 and DXS1003
(18.6-cM)
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X-inactivation pattern between normal and
carrier/affected
Skewed X-inactivation patterns in affected
haplotype or unaffected haplotype
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Treatments

• Currently no treatments available
• CN does not appear to interfere with visual
  function.
• DellOsso and Jacobs characterized the ocular
  oscillations of CN over a 35 year study published
  in July 2004

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Treatments (cont.)

• DellOsso 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

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Questions?
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References

• 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 641141-1146, 1999.
• 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.
• Jonathan B. Jacobs and Louis F. DellOsso.
  Congenital nystagmus Hypotheses for its genesis
  and complex waveforms within a behavioral ocular
  motor system model. Journal of Vision 4
  604-625, 2004.
• 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.