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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

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Congenital Nystagmus

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  1. Congenital Nystagmus Erik Twaroski Eye gifs from <http://www.omlab.org>

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

  3. Patterns of inheritance • autosomal dominant • autosomal recessive • X-linked dominant • X-linked recessive • X-linked dominant with incomplete penetrance

  4. Genes involved • PAX6 • NYS1

  5. 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

  6. PAX6 (cont.) Exons 4-13 contain coding regions. DNA binding domains and a linker.

  7. PAX6 mutations Sequence differences between normal and CN. Mutation creates a BsrI restriction site.

  8. Picture from Hanson et al.

  9. Mutation causing CN (Gly  Val) shown in yellow at the N-terminal domain

  10. 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>

  11. 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

  12. 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

  13. Picture from Cabot et al.

  14. 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

  15. Recombination events in parents of affected individuals Picture from Cabot et al.

  16. LOD scores for loci around NYS1

  17. Picture from Cabot et al.

  18. More statistical analysis Support forlocation of an X-linkedICN gene, with respectto three chromosome Xpmarkers. Likelihood estimates aregiven in log10. Distancesbetween marker loci, incentimorgans, are shown alongthe X-axis. The maximumlocation score for NYS1is between DXS8015 andDXS1003, over the locusDXS993. Picture from Cabot et al.

  19. Map of Xp Based on this NYS1 is between DXS8015 and DXS1003 (18.6-cM)

  20. X-inactivation pattern between normal and carrier/affected Skewed X-inactivation patterns in affected haplotype or unaffected haplotype

  21. 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

  22. 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

  23. Questions?

  24. 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 64:1141-1146, 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. 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. • 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.

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