Ten novel mutations found in aniridia

Wolf, Maija; Hemminki, Akseli; Kivioja, Aarne; Sistonen, Pertti; Kaitila, Ilkka; Ervasti, H.; Kinnunen, J.; Karaharju, Erkki; Knuutila, Sakari

doi:10.1002/(sici)1098-1004(1998)12:5<304::aid-humu3>3.3.co;2-y

Cited by 7 publications

(8 citation statements)

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“…In human patients, Peters' anomaly has been found to be associated with specific PAX6 mutations such as R26G(87) and G18W. (88) In addition, in humans, other factors appear to contribute to the specific phenotype of Peters' anomaly, as the G18W mutation is displayed as cataract or Peters' anomaly in different members of the same family. (88) A comparable familial variability has been observed in humans with the R26G mutation.…”

Section: Molecular Mechanisms Of Pax6 Haploinsufficiencymentioning

confidence: 89%

Anterior eye development and ocular mesenchyme: new insights from mouse models and human diseases

2004

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SummaryDuring development of the anterior eye segment, cells that originate from the surface epithelium or the neuroepithelium need to interact with mesenchymal cells, which predominantly originate from the neural crest. Failures of proper interaction result in a complex of developmental disorders such Peters' anomaly, Axenfeld-Rieger's syndrome or aniridia. Here we review the role of transcription factors that have been identified to be involved in the coordination of anterior eye development. Among these factors is PAX6, which is active in both epithelial and mesenchymal cells during ocular development, albeit at different doses and times. We propose that PAX6 is a key element that synchronizes the complex interaction of cell types of different origin, which are all needed for proper morphogenesis of the anterior eye. We discuss several molecular mechanisms that might explain the effects of haploinsufficiency of PAX6 and other transcription factors, and the broad variation of the resulting phenotypes.

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Section: Molecular Mechanisms Of Pax6 Haploinsufficiencymentioning

confidence: 89%

Anterior eye development and ocular mesenchyme: new insights from mouse models and human diseases

2004

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“…Data on point PAX6 mutations are from Prosser and van Heyningen [1998], Wolf et al [1998b], Love et al [1998], Gronskov et al [1999], and Chao et al [2000]. Major deletions, some of them involving both PAX6 and WT1 loci (WAGR syndrome) and others located closely to PAX6 exons but not including them, are responsible for C10% of cases [Wolf et al, 1998a;Lauderdale et al, 2000].…”

Section: à6mentioning

confidence: 99%

Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases

2002

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Communicated by Steve S. Sommer I estimate per nucleotide rates of spontaneous mutations of different kinds in humans directly from the data on per locus mutation rates and on sequences of de novo nonsense nucleotide substitutions, deletions, insertions, and complex events at eight loci causing autosomal dominant diseases and 12 loci causing X-linked diseases. The results are in good agreement with indirect estimates, obtained by comparison of orthologous human and chimpanzee pseudogenes. The average direct estimate of the combined rate of all mutations is 1.8 Â 10 À8 per nucleotide per generation, and the coefficient of variation of this rate across the 20 loci is 0.53. Single nucleotide substitutions are B25 times more common than all other mutations, deletions are Bthree times more common than insertions, complex mutations are very rare, and CpG context increases substitution rates by an order of magnitude. There is only a moderate tendency for loci with high per locus mutation rates to also have higher per nucleotide substitution rates, and per nucleotide rates of deletions and insertions are statistically independent on the per locus mutation rate. Rates of different kinds of mutations are strongly correlated across loci. Mutational hot spots with per nucleotide rates above 5 Â 10 À7 make only a minor contribution to human mutation. In the next decade, direct measurements will produce a rather precise, quantitative description of human spontaneous mutation at the DNA level. Hum Mutat 21:12-27,

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“…The protein contains the (conventional) 128-residue paired domain and five subsequent residues (SEKQQ) from Pax6. Lines below these sequences indicate residues that are conserved in almost all paired domains and also show missense mutations in the Pax6 paired domain (Azuma et al 1996(Azuma et al , 1998Tang et al 1997;Prosser and van Heyningen 1998 and http://www.mrc.hgu.ac.uk/ Softdata/Pax6/ cited therein; Wolf et al 1998;Grønskov et al 1999;Hanson et al 1999;T. Glaser, pers.…”

Section: Major Groove Contacts Made By the Carboxy-terminal Hth Unitmentioning

confidence: 99%

“…Of the 18 Pax6 paired domain missense mutations known to us (Hanson et al 1994(Hanson et al , 1999Azuma et al 1996Azuma et al , 1998Tang et al 1997;Prosser and van Heyningen 1998 and http://www.mrc.hgu.ac.uk/Softdata/ Pax6/ cited therein; Wolf et al 1998;Grønskov et al 1999; T. Glaser, pers. comm.…”

Section: Correlation With Pax Developmental Mutantsmentioning

confidence: 99%

Crystal structure of the human Pax6 paired domain-DNA complex reveals specific roles for the linker region and carboxy-terminal subdomain in DNA binding

Xu¹,

Rould²,

Xu³

et al. 1999

Genes & Development

281

292

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Pax6, a transcription factor containing the bipartite paired DNA-binding domain, has critical roles in development of the eye, nose, pancreas, and central nervous system. The 2.5 Å structure of the human Pax6 paired domain with its optimal 26-bp site reveals extensive DNA contacts from the amino-terminal subdomain, the linker region, and the carboxy-terminal subdomain. The Pax6 structure not only confirms the docking arrangement of the amino-terminal subdomain as seen in cocrystals of the Drosophila Prd Pax protein, but also reveals some interesting differences in this region and helps explain the sequence specificity of paired domain-DNA recognition. In addition, this structure gives the first detailed information about how the paired linker region and carboxy-terminal subdomain contact DNA. The extended linker makes minor groove contacts over an 8-bp region, and the carboxy-terminal helix-turn-helix unit makes base contacts in the major groove. The structure and docking arrangement of the carboxy-terminal subdomain of Pax6 is remarkably similar to that of the amino-terminal subdomain, and there is an approximate twofold symmetry axis relating the polypeptide backbones of these two helix-turn-helix units. Our structure of the Pax6 paired domain-DNA complex provides a framework for understanding paired domain-DNA interactions, for analyzing mutations that map in the linker and carboxy-terminal regions of the paired domain, and for modeling protein-protein interactions of the Pax family proteins.

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Ten novel mutations found in aniridia

Cited by 7 publications

References 0 publications

Anterior eye development and ocular mesenchyme: new insights from mouse models and human diseases

Anterior eye development and ocular mesenchyme: new insights from mouse models and human diseases

Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases

Crystal structure of the human Pax6 paired domain-DNA complex reveals specific roles for the linker region and carboxy-terminal subdomain in DNA binding

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