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A novel missense mutation in the paired domain of PAX9 causes non-syndromic oligodontia 总被引:15,自引:0,他引:15
Jumlongras D Lin JY Chapra A Seidman CE Seidman JG Maas RL Olsen BR 《Human genetics》2004,114(3):242-249
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PAX6, paired domain influences sequence recognition by the homeodomain 总被引:10,自引:0,他引:10
Mishra R Gorlov IP Chao LY Singh S Saunders GF 《The Journal of biological chemistry》2002,277(51):49488-49494
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Anita L. DeStefano L. Adrienne Cupples Kathleen S. Arnos J. H. Jr. Asher Clinton T. Baldwin Susan Blanton Melisa L. Carey Elias O. da Silva T. B. Friedman Jacquie Greenberg Anil K. Lalwani Aubrey Milunsky Walter E. Nance Arti Pandya Rajkumar S. Ramesar Andrew P. Read May Tassabejhi Edward R. Wilcox L. A. Farrer 《Human genetics》1998,102(5):499-506
Waardenburg syndrome (WS) type 1 is an autosomal dominant disorder characterized by sensorineural hearing loss, pigmentary
abnormalities of the eye, hair, and skin, and dystopia canthorum. The phenotype is variable and affected individuals may exhibit
only one or a combination of several of the associated features. To assess the relationship between phenotype and gene defect,
clinical and genotype data on 48 families (271 WS individuals) collected by members of the Waardenburg Consortium were pooled.
Forty-two unique mutations in the PAX3 gene, previously identified in these families, were grouped in five mutation categories: amino acid (AA) substitution in
the paired domain, AA substitution in the homeodomain, deletion of the Ser-Thr-Pro-rich region, deletion of the homeodomain
and the Ser-Thr-Pro-rich region, and deletion of the entire gene. These mutation classes are based on the structure of the
PAX3 gene and were chosen to group mutations predicted to have similar defects in the gene product. Association between mutation
class and the presence of hearing loss, eye pigment abnormality, skin hypopigmentation, or white forelock was evaluated using
generalized estimating equations, which allowed for incorporation of a correlation structure that accounts for potential similarity
among members of the same family. Odds for the presence of eye pigment abnormality, white forelock, and skin hypopigmentation
were 2, 8, and 5 times greater, respectively, for individuals with deletions of the homeodomain and the Pro-Ser-Thr-rich region
compared to individuals with an AA substitution in the homeodomain. Odds ratios that differ significantly from 1.0 for these
traits may indicate that the gene products resulting from different classes of mutations act differently in the expression
of WS. Although a suggestive association was detected for hearing loss with an odds ratio of 2.6 for AA substitution in the
paired domain compared with AA substitution in the homeodomain, this odds ratio did not differ significantly from 1.0.
Received: 27 July 1997 / Accepted: 9 December 1997 相似文献
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Singh S Stellrecht CM Tang HK Saunders GF 《The Journal of biological chemistry》2000,275(23):17306-17313
PAX6 is required for proper development of the eye, central nervous system, and nose. PAX6 has two DNA binding domains, a glycine-rich region that links the two DNA binding domains, and a transactivation domain. There is evidence that the different DNA binding domains of PAX6 have different target genes. However, it is not clear if the two DNA binding domains function independently. We have studied the effect of structural changes in the paired domain on the function of PAX6 mediated through its homeodomain. The R26G and I87R mutations have been reported in different human patients with clinically different phenotypes and are in the N- and the C-terminal halves of the paired domain, respectively. Surprisingly, we found that the I87R mutant protein not only lost the transactivation function but also failed to bind DNA by either of its DNA binding domains. In contrast, the R26G mutant protein lost DNA binding through its paired domain but had greater DNA binding and transactivation than wild-type PAX6 on homeodomain binding sites. Like R26G, the 5a isoform showed higher DNA binding than wild-type PAX6. This study demonstrates that the two subdomains of the paired domain influence the function of the homeodomain differentially and also provides an explanation for the difference in phenotypes associated with these mutations. 相似文献
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RhoA activation promotes transformation and loss of thyroid cell differentiation interfering with thyroid transcription factor-1 activity. 总被引:1,自引:0,他引:1
Diego L Medina Marcos Rivas Patricia Cruz Isabel Barroso Javier Regadera Pilar Santisteban 《Molecular endocrinology (Baltimore, Md.)》2002,16(1):33-44
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Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I). 总被引:20,自引:6,他引:14
C F Hoth A Milunsky N Lipsky R Sheffer S K Clarren C T Baldwin 《American journal of human genetics》1993,52(3):455-462
Waardenburg syndrome type I (WS-I) is an autosomal dominant disorder characterized by sensorineural hearing loss, dystopia canthorum, pigmentary disturbances, and other developmental defects. Klein-Waardenburg syndrome (WS-III) is a disorder with many of the same characteristics as WS-I and includes musculoskeletal abnormalities. We have recently reported the identification and characterization of one of the first gene defects, in the human PAX3 gene, which causes WS-I. PAX3 is a DNA-binding protein that contains a structural motif known as the paired domain and is believed to regulate the expression of other genes. In this report we describe two new mutations, in the human PAX3 gene, that are associated with WS. One mutation was found in a family with WS-I, while the other mutation was found in a family with WS-III. Both mutations were in the highly conserved paired domain of the human PAX3 gene and are similar to other mutations that cause WS. The results indicate that mutations in the PAX3 gene can cause both WS-I and WS-III. 相似文献