This iPSC line will be an important tool for retinal differentiation studies to better understand the CRD phenotype caused by the mutant p.Arg41Trp CRX protein.
Two point mutations of Crx, R41W and E80A, that cause cone-rod dystrophy in humans and lie within the homeodomain but outside the NLS did not disrupt the nuclear localization of Crx protein, but a R90W mutation of Crx that causes human Leber congenital amaurosis (LCA) and resides within the NLS resulted in the fusion protein localized in both nuclei and cytoplasm in majority (51% to 69%) of the transfected cells.
The missense change Val242Met was found in an isolate case of CORD and no controls; however, its pathogenicity remains uncertain because only limited segregation analysis was possible.
As an example, we discover an unannotated Tf_Otx Pfam domain on the cone rod homeobox protein, which suggests a possible mechanism for how the V242M mutation on this protein causes cone-rod dystrophy.
The Arg41Gln was associated with a late-onset, slowly progressing mild form of cone-rod dystrophy with cone loss but preserved rod and cone sensitivity until later in life.
Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function.
Although most heterozygous pathogenic variants in CRX are associated with autosomal dominant retinal degeneration, a homozygous c.268C> T (p.Arg90Trp) substitution and homozygous complete deletion of CRX have been reported to cause Leber congenital amaurosis.
Two point mutations of Crx, R41W and E80A, that cause cone-rod dystrophy in humans and lie within the homeodomain but outside the NLS did not disrupt the nuclear localization of Crx protein, but a R90W mutation of Crx that causes human Leber congenital amaurosis (LCA) and resides within the NLS resulted in the fusion protein localized in both nuclei and cytoplasm in majority (51% to 69%) of the transfected cells.
These data suggest that the R90W mutation results in a CRX protein with reduced DNA binding and transcriptional regulatory activity and that the subsequent changes in photoreceptor gene expression lead to the very early onset severe visual impairment in LCA.
Two point mutations of Crx, R41W and E80A, that cause cone-rod dystrophy in humans and lie within the homeodomain but outside the NLS did not disrupt the nuclear localization of Crx protein, but a R90W mutation of Crx that causes human Leber congenital amaurosis (LCA) and resides within the NLS resulted in the fusion protein localized in both nuclei and cytoplasm in majority (51% to 69%) of the transfected cells.
Two point mutations of Crx, R41W and E80A, that cause cone-rod dystrophy in humans and lie within the homeodomain but outside the NLS did not disrupt the nuclear localization of Crx protein, but a R90W mutation of Crx that causes human Leber congenital amaurosis (LCA) and resides within the NLS resulted in the fusion protein localized in both nuclei and cytoplasm in majority (51% to 69%) of the transfected cells.
Two point mutations of Crx, R41W and E80A, that cause cone-rod dystrophy in humans and lie within the homeodomain but outside the NLS did not disrupt the nuclear localization of Crx protein, but a R90W mutation of Crx that causes human Leber congenital amaurosis (LCA) and resides within the NLS resulted in the fusion protein localized in both nuclei and cytoplasm in majority (51% to 69%) of the transfected cells.
These data suggest that the R90W mutation results in a CRX protein with reduced DNA binding and transcriptional regulatory activity and that the subsequent changes in photoreceptor gene expression lead to the very early onset severe visual impairment in LCA.
As seen in human patients, heterozygous E168d2 ("E168d2/+") but not R90W ("R90W/+") mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration.
The Arg41Gln was associated with a late-onset, slowly progressing mild form of cone-rod dystrophy with cone loss but preserved rod and cone sensitivity until later in life.
The Arg41Gln was associated with a late-onset, slowly progressing mild form of cone-rod dystrophy with cone loss but preserved rod and cone sensitivity until later in life.