Disease progression in autosomal dominant cone–rod dystrophy caused by a novel mutation (D100G) in the GUCA1A gene

Lee, Winston; Merriam, Joanna E.; Allikmets, Rando; Tsang, Stephen H.

doi:10.1007/s10633-013-9420-z

Cited by 26 publications

(23 citation statements)

References 35 publications

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“…4 and Supplementary Tables T1-T3 ). The dynamic analysis performed with PyInteraph highlighted the constant presence of D64 and D100 among the highest-degree hubs, a particularly important result since D100 is the target of the cone-dystrophy related D100E/G mutations 17 41 . Other residues target of retinal dystrophy-associated point mutations were found among high-degree hubs both in the GC activating and inhibiting states of mGCAP1 and, to a lower extent, of nmGCAP1 ( Supplementary Tables T1 and T2).…”

Section: Discussionmentioning

confidence: 99%

Allosteric communication pathways routed by Ca2+/Mg2+ exchange in GCAP1 selectively switch target regulation modes

Marino

Dell’Orco

2016

Sci Rep

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GCAP1 is a neuronal calcium sensor protein that regulates the phototransduction cascade in vertebrates by switching between activator and inhibitor of the target guanylate cyclase (GC) in a Ca2+-dependent manner. We carried out exhaustive molecular dynamics simulations of GCAP1 and determined the intramolecular communication pathways involved in the specific GC activator/inhibitor switch. The switch was found to depend on the Mg2+/Ca2+ loading states of the three EF hands and on the way the information is transferred from each EF hand to specific residues at the GCAP1/GC interface. Post-translational myristoylation is fundamental to mediate long range allosteric interactions including the EF2-EF4 coupling and the communication between EF4 and the GC binding interface. Some hubs in the identified protein network are the target of retinal dystrophy mutations, suggesting that the lack of complete inhibition of GC observed in many cases is likely due to the perturbation of intra/intermolecular communication routes.

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Section: Discussionmentioning

confidence: 99%

Allosteric communication pathways routed by Ca2+/Mg2+ exchange in GCAP1 selectively switch target regulation modes

Marino

Dell’Orco

2016

Sci Rep

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“…When the 30 Hz-flicker amplitudes were lower than five microvolts or predicted to be lower than five microvolts based on exam, Burian-Allen contact lens electrodes were used to record the 30 Hz-flicker responses that are subsequently processed through narrow band-passed filtering with computed averaging 26 , 44 , 46 , 47 . The amplitudes obtained from both eyes were measured by a single user with Espion V6.0.56 software (Diagnosys LLC, Lowell, MA, USA), which calculates the amplitude from trough to peak of the first visible waveform, as performed previously 46 , 48 – 50 . Amplitudes of both eyes were averaged and compared between the two groups.…”

Section: Methodsmentioning

confidence: 99%

Electroretinography Reveals Difference in Cone Function between Syndromic and Nonsyndromic USH2A Patients

Sengillo

Cabral

Schuerch

et al. 2017

Sci Rep

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Usher syndrome is an inherited and irreversible disease that manifests as retinitis pigmentosa (RP) and bilateral neurosensory hearing loss. Mutations in Usherin 2A (USH2A) are not only a frequent cause of Usher syndrome, but also nonsyndromic RP. Although gene- and cell-based therapies are on the horizon for RP and Usher syndrome, studies characterizing natural disease are lacking. In this retrospective analysis, retinal function of USH2A patients was quantified with electroretinography. Both groups had markedly reduced rod and cone responses, but nonsyndromic USH2A patients had 30 Hz-flicker electroretinogram amplitudes that were significantly higher than syndromic patients, suggesting superior residual cone function. There was a tendency for Usher syndrome patients to have a higher distribution of severe mutations, and alleles in this group had a higher odds of containing nonsense or frame-shift mutations. These data suggest that the previously reported severe visual phenotype seen in syndromic USH2A patients could relate to a greater extent of cone dysfunction. Additionally, a genetic threshold may exist where mutation burden relates to visual phenotype and the presence of hearing deficits. The auditory phenotype and allelic hierarchy observed among patients should be considered in prospective studies of disease progression and during enrollment for future clinical trials.

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“…Mutations in GUCA1A, encoding for GCAP1 result in aberrant GC regulation and in retinal degeneration, a set of progressive diseases involving cones, the macula, and in some cases rods, ultimately leading to blindness [11][12][13]. To date, 20 GCAP1 variants have been associated with retinal dystrophy [14][15][16][17][18][19][20][21][22][23][24][25], with one of the most recently discovered being the G86R mutation, located in the previously mentioned hinge region [26]. Biochemical experiments performed with the GC-GCAP1 reconstituted system in the presence of the G86R mutation showed that the complex forms with higher affinity than the WT and it is unable to decelerate the GC at high Ca 2+ -levels corresponding to the dark-adapted state [26].…”

Section: Introductionmentioning

confidence: 99%

Constitutive Activation of Guanylate Cyclase by the G86R GCAP1 Variant Is Due to “Locking” Cation-π Interactions that Impair the Activator-to-Inhibitor Structural Transition

Abbas

Marino

Bielefeld

et al. 2020

IJMS

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Guanylate Cyclase activating protein 1 (GCAP1) mediates the Ca2+-dependent regulation of the retinal Guanylate Cyclase (GC) in photoreceptors, acting as a target inhibitor at high [Ca2+] and as an activator at low [Ca2+]. Recently, a novel missense mutation (G86R) was found in GUCA1A, the gene encoding for GCAP1, in patients diagnosed with cone-rod dystrophy. The G86R substitution was found to affect the flexibility of the hinge region connecting the N- and C-domains of GCAP1, resulting in decreased Ca2+-sensitivity and abnormally enhanced affinity for GC. Based on a structural model of GCAP1, here, we tested the hypothesis of a cation-π interaction between the positively charged R86 and the aromatic W94 as the main mechanism underlying the impaired activator-to-inhibitor conformational change. W94 was mutated to F or L, thus, resulting in the double mutants G86R+W94L/F. The double mutants showed minor structural and stability changes with respect to the single G86R mutant, as well as lower affinity for both Mg2+ and Ca2+, moreover, substitutions of W94 abolished “phase II” in Ca2+-titrations followed by intrinsic fluorescence. Interestingly, the presence of an aromatic residue in position 94 significantly increased the aggregation propensity of Ca2+-loaded GCAP1 variants. Finally, atomistic simulations of all GCAP1 variants in the presence of Ca2+ supported the presence of two cation-π interactions involving R86, which was found to act as a bridge between W94 and W21, thus, locking the hinge region in an activator-like conformation and resulting in the constitutive activation of the target under physiological conditions.

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Disease progression in autosomal dominant cone–rod dystrophy caused by a novel mutation (D100G) in the GUCA1A gene

Cited by 26 publications

References 35 publications

Allosteric communication pathways routed by Ca2+/Mg2+ exchange in GCAP1 selectively switch target regulation modes

Allosteric communication pathways routed by Ca2+/Mg2+ exchange in GCAP1 selectively switch target regulation modes

Electroretinography Reveals Difference in Cone Function between Syndromic and Nonsyndromic USH2A Patients

Constitutive Activation of Guanylate Cyclase by the G86R GCAP1 Variant Is Due to “Locking” Cation-π Interactions that Impair the Activator-to-Inhibitor Structural Transition

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