Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX

Rivolta, Carlo; Berson, Eliot L.; Dryja, Thaddeus P.

doi:10.1002/humu.1226

Cited by 90 publications

(71 citation statements)

References 41 publications

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“…OTX2, CRX, and NRL are key transcriptional regulators guiding rod and cone differentiation. Here, we determine a direct role of OTX2 in initiating and maintaining the transcription of Nrl in developing rod photoreceptors by taking advantage of a newly discovered mouse mutant trant and act in a dominant manner (47,48). 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.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Subsequent genetic screens not only identified CRX mutations in autosomal dominant cone-rod dystrophy (Freund et al, 1997), but also in autosomal dominant retinitis pigmentosa (adRP) (Sohocki et al, 1998) and Leber's congenital amaurosis (LCA) Rivolta et al, 2001b). Most CRX mutations are inherited in an autosomal dominant manner or occur de novo, particularly in LCA cases (Rivolta et al, 2001a). Many mutations are nucleotide insertions or deletions resulting in formation of a premature stop codon 3' of the mutated sites, which produce C-terminal truncated forms of CRX.…”

Section: Human Genetic Studiesmentioning

confidence: 99%

“…Many mutations are nucleotide insertions or deletions resulting in formation of a premature stop codon 3' of the mutated sites, which produce C-terminal truncated forms of CRX. Others are missense mutations, several of which are located in the homeodomain [ (Rivolta et al, 2001a); see Figure 1]. In vitro functional analysis demonstrated that many of the disease-linked mutations altered the ability of CRX to bind to DNA (homeodomain mutations) and/or activate transcription of the rhodopsin gene .…”

Section: Human Genetic Studiesmentioning

confidence: 99%

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

2008

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Rod and cone photoreceptors in the mammalian retina are special types of neurons that are responsible for phototransduction, the first step of vision. Development and maintenance of photoreceptors require precisely regulated gene expression. This regulation is mediated by a network of photoreceptor transcription factors centered on Crx, an Otx-like homeodomain transcription factor. The cell type (subtype) specificity of this network is governed by factors that are preferentially expressed by rods or cones or both, including the rod-determining factors neural retina leucine zipper protein (Nrl) and the orphan nuclear receptor Nr2e3; and cone-determining factors, mostly nuclear receptor family members. The best-documented of these include thyroid hormone receptor β2 (Trβ2), retinoid related orphan receptor Rorβ, and retinoid X receptor Rxrγ. The appropriate function of this network also depends on general transcription factors and co-factors that are ubiquitously expressed, such as the Sp zinc finger transcription factors and STAGA coactivator complexes. These cell type-specific and general transcription regulators form complex interactomes; mutations that interfere with any of the interactions can cause photoreceptor development defects or degeneration. In this manuscript, we review recent progress on the roles of various photoreceptor transcription factors and interactions in photoreceptor subtype development. We also provide evidence of auto-, para-, and feedback regulation among these factors at the transcriptional level. These protein-protein and protein-promoter interactions provide precision and specificity in controlling photoreceptor subtype-specific gene expression, development and survival. Understanding these interactions may provide insights to more effective therapeutic interventions for photoreceptor diseases.

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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.…”

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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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Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX

Cited by 90 publications

References 41 publications

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

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

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

The orphan nuclear hormone receptor ERR β controls rod photoreceptor survival

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