The autosome dominant disorders, ring dermoid of the cornea (RDC), iris hypolasia (IH) and Axenfeld-Rieger syndrome (ARS), are allelic disor- ders, as all three can result from mutations of the transcriptional factor ...The autosome dominant disorders, ring dermoid of the cornea (RDC), iris hypolasia (IH) and Axenfeld-Rieger syndrome (ARS), are allelic disor- ders, as all three can result from mutations of the transcriptional factor PITX2. Among three disorder phenotypes, ARS is the most severe, IH is milder than ARS, and RDC is the mildest. Missense muta- tions of the PITX2 homeodomain identified in RDC (R62H), IH (R84W) and ARS patients (T68P) were introduced into PITX2 cDNA by site-directed mutagenesis. PITX2 mutant proteins expressed in eucaryotic cells were stable and localized to the nu- cleus. Analysis of these mutant PITX2 proteins by DNA-binding shift and transactivation studies dem- onstrated that the R62H had the most activity in both studies, and the R84W still retained somewhat func- tions, whereas the T68P proved to be non-functional. These results are consistent with previous hypothesis that varying amount of residual PITX2 mutant activity could underline the severity of these phenotypes.展开更多
基金This work was supported by the National Natural Science Foundation of China （Grant No. 30500260）.
文摘The autosome dominant disorders, ring dermoid of the cornea (RDC), iris hypolasia (IH) and Axenfeld-Rieger syndrome (ARS), are allelic disor- ders, as all three can result from mutations of the transcriptional factor PITX2. Among three disorder phenotypes, ARS is the most severe, IH is milder than ARS, and RDC is the mildest. Missense muta- tions of the PITX2 homeodomain identified in RDC (R62H), IH (R84W) and ARS patients (T68P) were introduced into PITX2 cDNA by site-directed mutagenesis. PITX2 mutant proteins expressed in eucaryotic cells were stable and localized to the nu- cleus. Analysis of these mutant PITX2 proteins by DNA-binding shift and transactivation studies dem- onstrated that the R62H had the most activity in both studies, and the R84W still retained somewhat func- tions, whereas the T68P proved to be non-functional. These results are consistent with previous hypothesis that varying amount of residual PITX2 mutant activity could underline the severity of these phenotypes.
