Functional analysis of cone-rod homeobox (CRX) mutations associated with retinal dystrophy

Chen, Shiming; Wang, Qing Liang; Xu, Shuai; Liu, Ivy; Li, Lili Y.; Wang, Yufang; Zack, Donald J.

doi:10.1093/hmg/11.8.873

Cited by 76 publications

(104 citation statements)

References 31 publications

(41 reference statements)

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“…The p.G255fs mutation in Crx Rip mice (as in several dominant LCA patients) removes the C-terminal Otx-like domain of CRX and instead adds 133 unrelated residues. As the truncated CRX 1-254 protein retains DNA binding and transactivation properties consistent with a previous study of CRX functional domains (49), the addition of unrelated residues in CRX Rip protein must interfere with the function of CRX WT and OTX2 proteins (as discussed earlier). As two dominant LCA-causing mutations examined here mimic the Crx Rip/+ phenotype, our studies provide a plausible molecular mechanism for congenital blindness in dominant CRX-LCA.…”

Section: Discussionsupporting

confidence: 77%

OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

Roger¹,

Hiriyanna²,

Gotoh³

et al. 2014

J. Clin. Invest.

106

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Leber congenital amaurosis (LCA) encompasses a set of early-onset blinding diseases that are characterized by vision loss, involuntary eye movement, and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA, which is typically recessive; however, mutations in homeodomain transcription factor CRX lead to an autosomal dominant form of LCA. The mechanism of CRX-associated LCA is not understood. Here, we identified a spontaneous mouse mutant with a frameshift mutation in Crx (Crx Rip ). We determined that Crx Rip is a dominant mutation that results in congenital blindness with nonrecordable response by ERG and arrested photoreceptor differentiation with no associated degeneration. Expression of LCA-associated dominant CRX frameshift mutations in mouse retina mimicked the Crx Rip phenotype, which was rescued by overexpression of WT CRX. Whole-transcriptome profiling using deep RNA sequencing revealed progressive and complete loss of rod differentiation factor NRL in Crx Rip retinas. Expression of NRL partially restored rod development in Crx Rip/+ mice. We show that the binding of homeobox transcription factor OTX2 at the Nrl promoter was obliterated in Crx Rip mice and ectopic expression of OTX2 rescued the rod differentiation defect. Together, our data indicate that OTX2 maintains Nrl expression in developing rods to consolidate rod fate. Our studies provide insights into CRX mutation-associated congenital blindness and should assist in therapeutic design.

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Section: Discussionsupporting

confidence: 77%

OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

Roger¹,

Hiriyanna²,

Gotoh³

et al. 2014

J. Clin. Invest.

106

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“…Biochemical analysis has indicated that these factors are present at the promoters of rod-specific genes in vivo and directly activate expression of rod-specific genes (1,8,9). Mutation of rod-enriched transcription factors in humans can lead to rod photoreceptor dystrophy (10,11). Failure to express normal levels of rodspecific genes thus results in rod photoreceptor degeneration, and correction of this defect may have considerable value in treating inherited blindness.…”

mentioning

confidence: 99%

The orphan nuclear hormone receptor ERR β controls rod photoreceptor survival

Onishi

Peng

Poth

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mutation of rod photoreceptor-enriched transcription factors is a major cause of inherited blindness. We identified the orphan nuclear hormone receptor estrogen-related receptor β (ERRβ) as selectively expressed in rod photoreceptors. Overexpression of ERRβ induces expression of rod-specific genes in retinas of wild-type as well as Nrl −/− mice, which lack rod photoreceptors. Mutation of ERRβ results in dysfunction and degeneration of rods, whereas inverse agonists of ERRβ trigger rapid rod degeneration, which is rescued by constitutively active mutants of ERRβ. ERRβ coordinates expression of multiple genes that are rate-limiting regulators of ATP generation and consumption in photoreceptors. Furthermore, enhancing ERRβ activity rescues photoreceptor defects that result from loss of the photoreceptor-specific transcription factor Crx. Our findings demonstrate that ERRβ is a critical regulator of rod photoreceptor function and survival, and suggest that ERRβ agonists may be useful in the treatment of certain retinal dystrophies.T he vertebrate retina contains two major subtypes of photoreceptors-rods and cones. Clinically, dysfunction and death of rod photoreceptors are the primary causes of most forms of inherited photoreceptor dystrophy. A number of rod-expressed transcription factors (1-7) have been identified that are required for rod photoreceptor differentiation or survival. Biochemical analysis has indicated that these factors are present at the promoters of rod-specific genes in vivo and directly activate expression of rod-specific genes (1,8,9). Mutation of rod-enriched transcription factors in humans can lead to rod photoreceptor dystrophy (10, 11). Failure to express normal levels of rodspecific genes thus results in rod photoreceptor degeneration, and correction of this defect may have considerable value in treating inherited blindness.Analysis of gene expression in developing and mature rod photoreceptors has indicated that other transcription factors also show highly rod-enriched expression (12-15). Among these is estrogen-related receptor β (ERRβ), an orphan nuclear hormone receptor homologous to the classical estrogen receptor but which constitutively activates transcription in the absence of estradiol (16,17). ERRβ is specifically expressed in differentiating and mature mouse rod photoreceptors (12, 13), with significant mRNA levels also detected in the human retina (18). Deletion of a floxed allele of ERRβ in the embryoid body using a Sox2-Cre line (hereafter referred to as ERRβ −/− ) results in mice with a defect in inner ear development but no obvious retinal defects (19). Loss-of-function mutations of ERRβ have been reported in inherited forms of human deafness (20).Given the prominent expression of ERRβ in retinal photoreceptors, we hypothesized that ERRβ might also play an important role in rod photoreceptor function. We observed that genetic or pharmacological disruption of function of ERRβ leads to rod photoreceptor degeneration. ERRβ also directly regulates expression of rod-specific gen...

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“…Mutations of the HD that increase the activity are unusual, but two reported examples are the CRX homeobox gene mutation E80A 45 and the NLR mutation S50T. 46 CRX is a transcription factor that is expressed in the rod and cone photoreceptors of the retina.…”

Section: Discussionmentioning

confidence: 99%

Molecular analysis of a human PAX6 homeobox mutant

et al. 2006

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Pax6 controls eye, pancreas and brain morphogenesis. In humans, heterozygous PAX6 mutations cause aniridia and various other congenital eye abnormalities. Most frequent PAX6 missense mutations are located in the paired domain (PD), while very few missense mutations have been identified in the homeodomain (HD). In the present report, we describe a molecular analysis of the human PAX6 R242T missense mutation, which is located in the second helix of the HD. It was identified in a male child with partial aniridia in the left eye, presenting as a pseudo-coloboma. Gel-retardation assays revealed that the mutant HD binds DNA as well as the wild-type HD. In addition, the mutation does not modify the DNA-binding properties of the PD. Cell transfection assays indicated that the steady-state levels of the full length mutant protein are higher than those of the wild-type one. In cotransfection assays a PAX6 responsive promoter is activated to a higher extent by the mutant protein than by the wild-type protein.In vitro limited proteolysis assays indicated that the presence of the mutation reduces the sensitivity to trypsin digestion. Thus, we suggest that the R242T human phenotype could be due to abnormal increase of PAX6 protein, in keeping with the reported sensitivity of the eye phenotype to increased PAX6 dosage.

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Functional analysis of cone-rod homeobox (CRX) mutations associated with retinal dystrophy

Cited by 76 publications

References 31 publications

OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

The orphan nuclear hormone receptor ERR β controls rod photoreceptor survival

Molecular analysis of a human PAX6 homeobox mutant

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