Novel<i>GUCA1A</i>Mutations Suggesting Possible Mechanisms of Pathogenesis in Cone, Cone-Rod, and Macular Dystrophy Patients

Kamenarova, Kunka; Cortón, Marta; Garcı́a-Sandoval, Blanca; José, Patrícia; Panchev, Valentín; Ávila-Fernández, Almudena; Lopez-Molina, Maria Isabel; Chakarova, Christina; Ayuso, Carmen; Bhattacharya, Shom Shanker

doi:10.1155/2013/517570

Cited by 28 publications

(26 citation statements)

References 48 publications

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“…The CD and CRDs display genetic and phenotypic heterogeneity rendering genetic diagnosis challenging. Colobomalike macular atrophy is a rare phenotypic association in CD and CRD, with variants identified in ADAM9 and GUCA1A in only a few cases [14,15]. Other IRDs associated with coloboma-like macular atrophy include North Carolina Macular dystrophy, early-onset retinitis pigmentosa and LCA [16][17][18].…”

Section: Discussionmentioning

confidence: 99%

NMNAT1 variants cause cone and cone-rod dystrophy

et al. 2017

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Cone and cone-rod dystrophies (CD and CRD, respectively) are degenerative retinal diseases that predominantly affect the cone photoreceptors. The underlying disease gene is not known in approximately 75% of autosomal recessive cases. Variants in NMNAT1 cause a severe, early-onset retinal dystrophy called Leber congenital amaurosis (LCA). We report two patients where clinical phenotyping indicated diagnoses of CD and CRD, respectively. NMNAT1 variants were identified, with Case 1 showing an extremely rare homozygous variant c.[271G > A] p.(Glu91Lys) and Case 2 compound heterozygous variants c.[53 A > G];[769G > A] p.(Asn18Ser);(Glu257Lys). The detailed variant analysis, in combination with the observation of an associated macular atrophy phenotype, indicated that these variants were disease-causing. This report demonstrates that the variants in NMNAT1 may cause CD or CRD associated with macular atrophy. Genetic investigations of the patients with CD or CRD should include NMNAT1 in the genes examined.

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Section: Discussionmentioning

confidence: 99%

NMNAT1 variants cause cone and cone-rod dystrophy

et al. 2017

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“…Another peculiar feature of the apo state was a conserved pair of H-bonds between the backbone groups NH of Ile 107 and C_O of Leu 151 and NH of Leu 153 and C_O of Gly 105, which created a short antiparallel β-sheet stable during the 200 ns simulation, which contributed to maintain EF3 and EF4 in an open conformation. Interestingly, both residues Ile 107 and Leu 151 have been found to be mutated respectively in Thr and Phe in patients suffering from cone dystrophy [47,48]. Another similarly short β-sheet was observed between EF1 and EF2, which however was not stable during the production phase.…”

Section: Structural Dynamics Of Putative Gc-activating States Over 20mentioning

confidence: 99%

Structural effects of Mg2+ on the regulatory states of three neuronal calcium sensors operating in vertebrate phototransduction

Marino

Sulmann

Koch

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The effects of physiological concentration of magnesium on the switch states of the neuronal calcium sensor proteins recoverin, GCAP1 and GCAP2 were investigated. Isothermal titration calorimetry was applied for binding studies. Circular dichroism spectroscopy was used to characterize protein thermal stability, secondary and tertiary structure in conditions of high and low [Ca²⁺], mimicking respectively the dark-adapted and light-exposed photoreceptor states during the phototransduction cascade. Further, molecular dynamics (MD) simulations were run to investigate the dynamical structural properties of GCAP1 in its activator, inhibitor and putative transitory states. Our results confirmed that Mg²⁺ is unable to trigger the typical Ca²⁺-induced conformational change of recoverin (myristoyl switch) while it decreases its thermal stability. Interestingly, Mg²⁺ seems to affect the conformation of GCAP2 both at high and low [Ca²⁺], however the variations are more substantial for myristoylated GCAP2 in the absence of Ca²⁺. GCAP1 is responsive to Mg²⁺ only in its low [Ca²⁺] state and Mg²⁺-GCAP1 tertiary structure slightly differs from both apo and Ca²⁺-bound states. Finally, MD simulations suggest that the GCAP1 state harboring one Mg²⁺ ion bound to EF2 acquires structural characteristics that are thought to be relevant for the activation of the guanylate cyclase. Moreover, all the putative Mg²⁺-bound states of myristoylated GCAP1 are structurally less flexible than Ca²⁺-bound states. GCAP1 acquires a more compact tertiary structure that is less accessible to the solvent, thereby inducing a different conformation to the myristoyl moiety, which might be crucial for the activation of the guanylate cyclase. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

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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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NovelGUCA1AMutations Suggesting Possible Mechanisms of Pathogenesis in Cone, Cone-Rod, and Macular Dystrophy Patients

Cited by 28 publications

References 48 publications

NMNAT1 variants cause cone and cone-rod dystrophy

NMNAT1 variants cause cone and cone-rod dystrophy

Structural effects of Mg2+ on the regulatory states of three neuronal calcium sensors operating in vertebrate phototransduction

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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