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
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 Xp 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 Recombination events indicated which markers were closely linked
Picture from Cabot et al. Recombination events in parents of affected individuals
LOD scores for loci around NYS1
Picture from Cabot et al.
Support for location of an X-linked ICN gene, with respect to three chromosome Xp markers. Likelihood estimates are given in log 10. 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. More statistical analysis
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
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: , 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 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: , 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.