<i>SPATA7</i>: Evolving phenotype from cone-rod dystrophy to retinitis pigmentosa

Matsui, Rodrigo; McGuigan, David B.; Gruzensky, Michaela; Alemán, Tomás S.; Schwartz, Sharon; Sumaroka, Alexander; Koenekoop, Robert K.; Cideciyan, Artur V.; Jacobson, Samuel G.

doi:10.3109/13816810.2015.1130154

Cited by 13 publications

(9 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the overall topography of the retinal dysfunction awaits confirmation in larger groups of patients with RDH12-IRDs, the pattern observed in this work, taken together with those of previous reports, strongly suggests that autosomal recessive mutations in RDH12 cause a predominantly severe central retinal degeneration that is consistent with an early CRD phenotype. 32,35,[54][55][56][57] Reports of CRD phenotypes in milder forms of RDH12-IRD supports a common disease expression with a wide spectrum of severity in RDH12-IRD. 32,44,55 The disease mechanisms in RDH12-IRD are not fully understood, but the severity and early presentation of the phenotype that results suggest a critical role in human retinal physiology.…”

Section: Discussionmentioning

confidence: 82%

RDH12Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function

Alemán

Uyhazi

Serrano

et al. 2018

Invest. Ophthalmol. Vis. Sci.

Self Cite

View full text Add to dashboard Cite

PURPOSE. To describe the retinal phenotype of pediatric patients with mutations in the retinol dehydrogenase 12 (RDH12) gene. METHODS. Twenty-one patients from 14 families (ages 2-17 years) with RDH12-associated inherited retinal degeneration (RDH12-IRD) underwent a complete ophthalmic exam and imaging with spectral domain optical coherence tomography (SD-OCT) and near infrared and short-wavelength fundus autofluorescence. Visual field extent was measured with Goldmann kinetic perimetry, visual thresholds with dark-adapted static perimetry or with dark-adapted chromatic full-field stimulus testing (FST) and transient pupillometry. RESULTS. Visual acuity ranged from 20/40 to light perception. There was parafoveal depigmentation or atrophic maculopathies accompanied by midperipheral intraretinal pigment migration. SD-OCT revealed foveal thinning in all patients and detectable but thinned outer nuclear layer (ONL) at greater eccentricities from the fovea. Photoreceptor outer segment (POS) signals were only detectable in small pockets within the central retina. Measurable kinetic visual fields were limited to small (<5-108) central islands of vision. Electroretinograms were reported as undetectable or severely reduced in amplitude. FST sensitivities to a 467 nm stimulus were rod-mediated and reduced on average by~2.5 log units. A thinned central ONL colocalized with severely reduced to nondetectable conemediated sensitivities. Pupillometry confirmed the psychophysically measured abnormalities. CONCLUSIONS. RDH12-IRD causes an early-onset, retina-wide disease with particularly severe central retinal abnormalities associated with relatively less severe rod photoreceptor dysfunction, a pattern consistent with an early-onset cone-rod dystrophy. Severely abnormal POS but detectable ONL in the pericentral and peripapillary retina suggest these regions may become targets for gene therapy.

show abstract

Section: Discussionmentioning

confidence: 82%

RDH12Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function

Alemán

Uyhazi

Serrano

et al. 2018

Invest. Ophthalmol. Vis. Sci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In retrospect this finding is maybe not surprising. Peripheral to TZ, retinal function is substantially reduced, ONL thickness is relatively retained while OS are very abnormal in many IRDs 12 , 87 , 93 , 103 , 104 . Structural abnormalities of the rod OS beyond that expected from loss of neighboring rod cells and functional abnormalities of the rod system beyond that expected from reduced OS volume could combine to contribute to the RFD.…”

Section: Discussionmentioning

confidence: 99%

Rod function deficit in retained photoreceptors of patients with class B Rhodopsin mutations

Cideciyan

Jacobson

Román

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

A common inherited retinal disease is caused by mutations in RHO expressed in rod photoreceptors that provide vision in dim ambient light. Approximately half of all RHO mutations result in a Class B phenotype where mutant rods are retained in some retinal regions but show severe degeneration in other regions. We determined the natural history of dysfunction and degeneration of retained rods by serially evaluating patients. Even when followed for more than 20 years, rod function and structure at some retinal locations could remain unchanged. Other locations showed loss of both vision and photoreceptors but the rate of rod vision loss was greater than the rate of photoreceptor degeneration. This unexpected divergence in rates with disease progression implied the development of a rod function deficit beyond loss of cells. The divergence of progression rates was also detectable over a short interval of 2 years near the health-disease transition in the superior retina. A model of structure-function relationship supported the existence of a large rod function deficit which was also most prominent near regions of health-disease transition. Our studies support the realistic therapeutic goal of improved night vision for retinal regions specifically preselected for rod function deficit in patients. Vision is initiated with the absorption of photons by opsin molecules located in the outer segment antenna of retinal photoreceptor cells. Resulting hyperpolarization of the photoreceptor plasma membrane activates inter-neuronal signaling pathways which reach the visual cortex culminating in perception. Any number of defects along the complex visual pathway can give rise to loss of vision. Monogenic defects causing inherited retinal diseases (IRDs) act primarily at retinal photoreceptors and provide an opportunity to understand detailed mechanism of vision loss. One of the most common IRDs is due to mutations in Rhodopsin (RHO) associated with autosomal dominant retinitis pigmentosa (adRP) 1-4. RHO encodes the opsin molecules expressed only in rod photoreceptors which provide night vision. Thus, the primary consequence of the molecular defect in RHO-adRP is abnormal night vision. Day vision mediated by cone photoreceptors are often affected secondarily through non-cell-autonomous mechanisms. There are currently no approved treatments for RHO-adRP, but promising therapeutic approaches directed to the rod photoreceptors include knock-down-and-replace gene therapy 5 , anti-sense oligonucleotides 6 , and modification of proteasomal activity 7. The human RHO-adRP disease phenotype is well represented by only two classes of mutations 8-13 despite the hypothesized existence of a variety of pathomechanisms in vitro 14,15. Patients with Class A phenotype have severe, early and retina-wide loss of rod photoreceptors with residual visual function originating only from cone cells. In Class B RHO phenotypes on the other hand, loss of rods is limited to certain retinal regions, or sectors, but rods (and cones) are retained in neighboring regi...

show abstract

“…Previously, we identified disease-causing mutations in SPATA7 , encoding spermatogenesis associated protein 7 (MIM 609868), in families with LCA and juvenile RP (Wang et al, 2009). Following this report, additional studies have identified SPATA7 mutations in patients with these diseases, clearly demonstrating a causal link between SPATA7 and human retinal disease (Kannabiran et al, 2012; Mackay et al, 2011; Matsui et al, 2016; Mayer et al, 2015; Perrault et al, 2010; Watson et al, 2014). Recently, we examined the effects of germline disruption of Spata7 and showed that Spata7 knockout (KO) mice exhibit early onset retinal degeneration, and the phenotype can be rescued by gene therapy (Eblimit et al, 2015; Zhong et al, 2015).…”

Section: Introductionmentioning

confidence: 62%

Conditional loss of Spata7 in photoreceptors causes progressive retinal degeneration in mice

Eblimit

Agrawal

Thomas

et al. 2018

Experimental Eye Research

View full text Add to dashboard Cite

The mammalian retina consists of multiple cell layers including photoreceptor cells, which are light sensing neurons that play essential functions in the visual process. Previously, we identified mutations in SPATA7, encoding spermatogenesis associated protein 7, in families with Leber Congenital Amaurosis (LCA) and juvenile Retinitis Pigmentosa (RP), and showed that Spata7 null mice recapitulate the human disease phenotype of retinal degeneration. SPATA7 is expressed in the connecting cilium of photoreceptor (PR) cells in the mouse retina, as well as in retinal pigment epithelium (RPE) cells, but the functional role of Spata7 in the RPE remains unknown. To investigate whether Spata7 is required in PRs, the RPE, or both, we conditionally knocked out Spata7 in photoreceptors and RPE cells using Crx-Cre and Best1-Cre transgenic mouse lines, respectively. In Spata7 photoreceptor-specific conditional (cKO) mice, both rod and cone photoreceptor dysfunction and degeneration is observed, characterized by progressive thinning of the outer nuclear layer and reduced response to light; however, RPE-specific deletion of Spata7 does not impair retinal function or cell survival. Furthermore, our findings show that both Rhodopsin and RPGRIP1 are mislocalized in the Spata7; Crx-Cre cKO mice, suggesting that loss of Spata7 in photoreceptors alone can result in altered trafficking of these proteins in the connecting cilium. Together, our findings suggest that loss of Spata7 in photoreceptors alone is sufficient to cause photoreceptor degeneration, but its function in the RPE is not required for photoreceptor survival; therefore, loss of Spata7 in photoreceptors alters both rod and cone function and survival, consistent with the clinical phenotypes observed in LCA and RP patients with mutations in SPATA7.

show abstract

SPATA7: Evolving phenotype from cone-rod dystrophy to retinitis pigmentosa

Cited by 13 publications

References 19 publications

RDH12Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function

RDH12Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function

Rod function deficit in retained photoreceptors of patients with class B Rhodopsin mutations

Conditional loss of Spata7 in photoreceptors causes progressive retinal degeneration in mice

Contact Info

Product

Resources

About