New Omics—Derived Perspectives on Retinal Dystrophies: Could Ion Channels-Encoding or Related Genes Act as Modifier of Pathological Phenotype?
Abstract
:1. Introduction
The Physiological Role of Main Ocular Ion Channel Types and Their Association to Eye-Related Diseases
2. Results
2.1. Clinical Examination of Family Probands Highlighted the Possible Impairment of Retinal Neurotransmission
2.2. Whole Exome Sequencing Data Analysis Revealed More than One Known Causative Variant of Retinal Dystrophies in Each Proband
2.3. The Complex Genotype-Phenotype Association Suggested the Possible Involvement of Modifier Genes Encoding Ion Channels
2.4. Biochemical Analyses Highlighted Possible Altered Chemical-Physical Features in Mutated Channels
2.5. 3D Structure Analysis of Mutated Channels Showed the Deletion or the Addition of Ion-Binding Sites
2.6. Pathways Analysis of Ion Channel-Related Mutated Genes Suggested a Complex Regulation of Synaptic Transmission Associated to Light Stimuli
2.7. Ion Channel-Related Mutated Genes and Known Causative Genes of Retinal Dystrophies Suggested a Complex Regulation Network of Interactors
3. Discussion
4. Materials and Methods
4.1. Clinical Data and Sample Collection
4.2. Whole Exome Sequencing and Data Analysis
4.3. Variant Filtering and Gene Prioritization
4.4. Variant Validation
4.5. Proteomic in-Silico Analyses
4.6. Pathway and Subpathway Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
IRDs | Inherited Retinal Dystrophies |
RPE | Retinal Pigment Epithelium |
RGCs | Retinal Ganglion Cells |
CFTR | Cystic Fibrosis Transmembrane Conductance Regulator |
LCA | Leber Congenital Amaurosis |
RP | Retinitis Pigmentosa |
ERG | Electroretinogram |
VEP | Visual Evoked Potential |
HGMD | Human Gene Mutation Database |
WES | Whole Exome Sequencing |
GO | Gene Ontology |
PTC | Premature Termination Codon |
AMPAR | AMPA Receptors |
BCVA | Best-Corrected Visual Acuity |
SD-OCT | Spectral-Domain Optical Coherence Tomography |
ISCEV | International Society for Clinical Electrophysiology of Vision |
PCR | Polymerase Chain Reaction |
RMSD | Root Mean Square Deviation |
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FEATURE | RP_2 | RP_20 | RP_21 | RP_25 | RP_32 | RP_37 | RP_38 |
---|---|---|---|---|---|---|---|
Age | 72 | 61 | 52 | 75 | 56 | 29 | 13 |
Sex | F | M | F | F | M | M | M |
Age of Onset | 4 | 8 | 4 | 24 | 10 | 9 | 3 |
Age of First Diagnosis | 16 | 16 | 16 | 16 | 16 | 9 | b |
Photophobia | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
Night Blindness | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
Color Vision | Altered | Present | Reduced | Reduced | Altered | Altered | Reduced |
Hearing Involvement | Yes | No | No | No | Yes | Yes | Yes |
Flashes of Lights | No | No | No | Yes | Yes | No | No |
White Flies | Yes | No | No | Yes | Yes | No | No |
ERG | Extinct | NA | Extinct (photopic) | Near extinction (photopic); extinct (scotopic) | Extinct (both photopic and scotopic) | Extinct (scotopic) | Quite reduced (both photopic and scotopic) |
VEP | NA | NA | Both VEP pattern and VEP flash very reduced amplitude and normal latency in both eyes | VEP pattern with huge P100 latency increase on the right, disrupted response on the left; VEP flash with bilateral latency quite increase | NA | NA | Intact visual pathways in both eyes |
Other | Peripheral vision, bilateral nystagmus | Altered perception of depth | Electrostimulation and magnetotherapy cleared visual perception and delayed degeneration; in relax situations visual perception is improved | Nystagmus | Tunnel vision; dizziness (with loss of balance); the intake of bananas improves visual acuity, especially the white vision | Generating cousins | Generating cousins; mild cerebellar atrophy; cone-rod dystrophy clinical diagnosis |
FEATURE | PHENOTYPE | RP_2 | RP_20 | RP_21 | RP_25 | RP_32 | RP_37 | RP_38 |
---|---|---|---|---|---|---|---|---|
GUCY2D | Cone-Rod Dystrophy | rs61750173 (p.R838H) | ||||||
rs138836357 (p.R365W) | ||||||||
ABCA4 | rs6666652 (p.S1047I) | rs6666652 (p.S1047I) | rs6666652 (p.S1047I) | |||||
C8orf37 | rs36096184 (p.P19S) | |||||||
RPGRIP | rs10151259 (p.A547S) | rs10151259 (p.A547S) | ||||||
MYO7A | Usher Syndrome | rs1052030 (p.L16Ter) | rs1052030 (p.L16Ter) | rs1052030 (p.L16Ter) | rs1052030 (p.L16Ter) | rs1052030 (p.L16Ter) | ||
rs77625410 (Y1719C) | ||||||||
PCDH15 | rs4935502 (p.D435A) | rs4935502 (p.D435A) | rs4935502 (p.D435A) | |||||
USH2A | rs696723 (p.G713S) | |||||||
SEMA4A | Retinitis Pigmentosa | rs41265017 (p.R713Q) | ||||||
CEP290 | rs183655276 (p.D1413H) | |||||||
AIPL1 | rs150427474 (p.R261Q) | |||||||
TRPM1 | Congenital Stationary Night Blindness | rs138886378 (p.S157F) | ||||||
CACNA1F | rs141159097 (p.N746T) | |||||||
BBS2 | Bardet-Biedl Syndrome | rs4784677 (p.S70N) | rs4784677 (p.S70N) | rs4784677 (p.S70N) | rs4784677 (p.S70N) | rs4784677 (p.S70N) | ||
CHM | Choroideremia | rs55741408 (p.L80F) |
GENE | GO Info | RP_2 | RP_20 | RP_21 | RP_25 | RP_32 | RP_37 | RP_38 |
---|---|---|---|---|---|---|---|---|
ANK2 | Required for Na+/K+-ATPase, Na+/Ca2+ exchanger and Beta-2-Spectrin expression; abundant in rods | I825T | ||||||
CACNA1A | The channel activity is directed by the pore-forming alpha-1 subunit, whereas the others act as auxiliary subunits. The isoform alpha-1A gives rise to P and/or Q-type calcium currents | Q792_Q800del | ||||||
CACNG8 | Modulates Ca2+ L-type channel activity and AMPAR opening | G327C; G361V | ||||||
CHRNA7 | Subunit of nicotinic ACh channel-receptor; it forms a homo-oligomeric channel with high permeability to Ca2+ | L166fs | L166fs | |||||
CLIC5 | Constitutes channel with low-selectivity, also for Cl− | S106ter | S106ter | S106ter | S106ter | |||
CNGB1 | Subunit of nonselective cationic ion channels mediated by cyclic nucleotides; abundant in rods | E370_E371del | ||||||
CNGB3 | Beta subunit of a cationic ion channel mediated by cyclic nucleotides; abundant in cones | R781C | R781C | R781C | R781C | R781C | ||
DRD4 | D4-subtype of dopamine receptors; abundant in retinal ganglion cells | D288G | ||||||
LRRK2 | Serine/threonine kinase which phosphorylates proteins involved into neuronal plasticity, autophagy and vesicular trafficking | P1262A | ||||||
PIEZO1 | Ion channel which boosts the intracellular entry of Ca2+ | V250A; K1878del |
Gene | Wt/Mutated | MW [g/moL] | Net Charge [pH = 7] | pI | Average Hydropathy | Aliphatic Index | A₂₈₀ (ox.) | A₂₈₀ (red.) | ε₂₈₀ [M−¹ cm−¹] | Instability Index | Features |
---|---|---|---|---|---|---|---|---|---|---|---|
ANK2 | Wt | 165,738.9 | −188.1 | 4.32 | −0.88 | 60.79 | 0.38 | 0.37 | 61,770 | 72.04 | EFO, CA, MG, OHX, MN, MG, NDP, MYR, CA, DCA, 43 helices, 62 strands |
I825T | 165,726.94 | −188.01 | 4.32 | −0.88 | 60.53 | 0.38 | 0.37 | 61,770 | 71.82 | 86 helices, 124 strands, I825T | |
CACNA1A | Wt | 225,243.55 | 34.65 | 9.14 | −0.59 | 68.01 | 0.99 | 0.99 | 222,890 | 53.1 | 9SL, ANP, III, MGE, Y01, CA, MG, 6OU, 61 helices, 4 strands |
Q792_Q800del | 218,047.31 | 36.67 | 9.22 | −0.60 | 68.10 | 0.97 | 0.97 | 211,430 | 52.29 | 9SL, III, CA, Y01, ANP, UUU, MG, MGE, 9Z9, 6OU, 74 helices | |
CACNG8 | Wt | 43,312.87 | 11.22 | 9.34 | −0.10 | 77.93 | 1.09 | 1.08 | 46,870 | 57.88 | ACD, BCL, XE, III, ZN, CVM, MG, NUC, CA, CA, 11 helices, 5 strands |
G327C; G361V | 43,401.04 | 11.16 | 9.29 | −0.08 | 78.61 | 1.09 | 1.08 | 46,870 | 57.21 | 22 helices, 10 strands, G327C, G361V | |
CHRNA7 | Wt | 56,449.44 | −6.91 | 6.02 | 0.08 | 95.10 | 1.76 | 1.74 | 98,320 | 44.56 | III, MLK, DSF, ZY5, EPJ, IVM, TC9, 10 helices, 12 strands |
L166fs | 23,812.21 | 0.21 | 6.95 | −0.31 | 86.44 | 2.71 | 2.7 | 64,400 | 47.42 | III, CU9, MLK, PLC, V11, 9Z0, 3 helices, 10 strands | |
CLIC5 | Wt | 46,502.65 | −29.41 | 4.71 | −0.69 | 73.32 | 0.95 | 0.94 | 43,780 | 45.83 | GSH, MNB, ASC, P10, GTX, GDS, CA, 12 helices, 6 strands |
S106ter | 12,409.07 | −22.62 | 3.97 | −1.21 | 60.66 | 1.20 | 1.20 | 14,900 | 56.84 | FE2, CA, MN, FAD, OXD, OXY, ZN, ACT, MN3, 1 helix, 3 strands | |
CNGB1 | Wt | 139,677.76 | −78.93 | 4.75 | −0.60 | 75.08 | 1.15 | 1.14 | 159,170 | 65.92 | CMP, ANP, 6ZL, CLA, PGW, III, CA, SF4, MG, 30 helices, 12 strands |
E370_E371del | 139,419.53 | −76.93 | 4.77 | −0.59 | 75.20 | 1.15 | 1.14 | 159,170 | 65.49 | CMP, B73, ANP, PGW, IAC, K, CLA, MG, CA, CH1, 28 helices, 11 strands | |
CNGB3 | Wt | 92,166.52 | 3.64 | 8.06 | −0.51 | 82.81 | 1.09 | 1.09 | 100,160 | 43.43 | CMP, PGW, CA, SF4, 78M, ANP, K, III, CLA, SF4, 29 helices, 13 strands |
R781C | 92,113.47 | 2.58 | 7.81 | −0.50 | 82.81 | 1.09 | 1.09 | 100,160 | 43.26 | 58 helices, 26 strands, R781C | |
DRD4 | Wt | 43,901.46 | 14.89 | 9.24 | 0.30 | 96.01 | 1.02 | 0.99 | 43,430 | 49.26 | AQD, ERC, NA, CLR, 1WV, CLR, 2CV, 2CV, SOG, CLR, 17 helices |
D288G | 43,843.43 | 15.88 | 9.31 | 0.31 | 96.01 | 1.02 | 0.99 | 43,430 | 48.81 | 34 helices, D288G | |
LRRK2 | Wt | 224,673.52 | −31.59 | 6.06 | −0.11 | 104.81 | 0.73 | 0.72 | 161,120 | 45.81 | CA, CLA, III, III, SE, UUU, MG, UUU, UUU, III, 98 helices, 4 strands |
P1262A | 224,647.49 | −30.59 | 6.06 | −0.11 | 104.85 | 0.73 | 0.72 | 161,120 | 45.65 | 196 helices, 8 strands, P1262A | |
PIEZO1 | Wt | 224,984.30 | −1.22 | 7.07 | 0.06 | 101.72 | 1.66 | 1.65 | 370,820 | 51.95 | ANP, 9SL, MGE, NUC, Y01, MG, III, 9Z9, CA, GRG, 79 helices, 4 strands |
V250A; K1878del | 226,789.15 | −4.13 | 6.85 | 0.06 | 101.34 | 1.65 | 1.64 | 370,820 | 51.55 | MGE, III, BCL, ANP, CA, P10, GRG, CLA, MG, 104 helices, 2 strands |
GENE | VARIANT | LIGAND BINDING SITE (Wt) [AA] | LIGAND BINDING SITE (Mut) [AA] | NOTES |
---|---|---|---|---|
ANK2 | I825T | EF0: 1498 Mg: 1499 F2A: 1500 NDP: 1501 Ca: 1502 | EF0: 1498 Mg: 1499 F2A: 1500 NDP: 1501 Ca: 1502 | Binding sites for all predicted ligands identical for wild and mutated proteins |
CACNA1A | Q792_Q800del | 9SL: 1997 ANP: 1998 Y01: 1999 Ca: 2000 Mg: 2001 6OU: 2002 | 9SL: 1937 Ca: 1938 Y01: 1939 ANP: 1940 9Z9: 1941 6OU: 1942 | Ca2+ binding sites almost shifted, deletion of a Mg2+ binding site in mutated protein |
CACNG8 | G327C; G361V | ACD: 426 BCL: 427 Ca: 430 XE: 428 Zn: 429 | ACD: 426 BCL: 427 Ca: 430 XE: 428 Zn: 429 | Binding sites for all predicted ligands identical for wild and mutated proteins |
CHRNA7 | L166fs | NH2: 503, 506, 509 MLK: 504 DSF: 505 ZY5: 507 EPJ: 508 IVM: 510 TC9: 511 | NH2: 206 Cu9: 207 9Z0: 208–209 | Deletion of several ligand binding sites in mutated protein |
CLIC5 | S106ter | GSH: 411, 415 GTT: 412 MNB: 413 ASC: 414 GTX: 416 GDS: 417 Ca: 418 | Fe2: 107 Mn: 108 Ca: 109 FAD: 110 OXD: 111 OXY: 112 Zn: 113 Mn3: 114 | Ca2+ binding sites almost shifted, creation of a several new ion binding sites in mutated protein |
CNGB1 | E370_E371del | Unknown: 1252-1264 ANP: 1265-1266 6ZL: 1267 CLA: 1268 PGW: 1269 SF4: 1270 Mg: 1271 | B73: 1250 ANP: 1251 PGW: 1252 IAC: 1253 K: 1254 CLA: 1255 Mg: 1256 Ca: 1257 CH1: 1258 | Mg2+ binding site almost shifted, creation of a K+ and Ca2+ binding sites in mutated protein |
CNGB3 | R781C | PGW: 810 Ca: 811 SF4: 812, 817 78M: 813 ANP: 814 K: 815 CLA: 816 | PGW: 810 Ca: 811 SF4: 812, 817 78M: 813 ANP: 814 K: 815 CLA: 816 | Binding sites for all predicted ligands identical for wild and mutated proteins |
DRD4 | D288G | AQD: 420 ERC: 421 Na: 422 CLR: 423, 425, 427 1WV: 424 WHJ: 426 | AQD: 420 ERC: 421 Na: 422 CLR: 423, 425, 427 1WV: 424 WHJ: 426 | Binding sites for all predicted ligands identical for wild and mutated proteins |
LRRK2 | P1262A | Unknown: 1981-1984 | Unknown: / | Variant near Mg2+ binding site, far from Se and Ca2+ ones |
PIEZO1 | V250A; K1878del | ANP: 1981 9SL: 1982 Y01: 1983 9Z9: 1984 Ca: 1985 | Unknown: 1999-2000 BCL: 2001 ANP: 2002 Ca: 2003 CLA: 2004 Mg: 2005 | Ca2+ binding sites almost shifted, creation of a Mg2+ binding site in mutated protein |
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Donato, L.; Scimone, C.; Alibrandi, S.; Abdalla, E.M.; Nabil, K.M.; D’Angelo, R.; Sidoti, A. New Omics—Derived Perspectives on Retinal Dystrophies: Could Ion Channels-Encoding or Related Genes Act as Modifier of Pathological Phenotype? Int. J. Mol. Sci. 2021, 22, 70. https://doi.org/10.3390/ijms22010070
Donato L, Scimone C, Alibrandi S, Abdalla EM, Nabil KM, D’Angelo R, Sidoti A. New Omics—Derived Perspectives on Retinal Dystrophies: Could Ion Channels-Encoding or Related Genes Act as Modifier of Pathological Phenotype? International Journal of Molecular Sciences. 2021; 22(1):70. https://doi.org/10.3390/ijms22010070
Chicago/Turabian StyleDonato, Luigi, Concetta Scimone, Simona Alibrandi, Ebtesam Mohamed Abdalla, Karim Mahmoud Nabil, Rosalia D’Angelo, and Antonina Sidoti. 2021. "New Omics—Derived Perspectives on Retinal Dystrophies: Could Ion Channels-Encoding or Related Genes Act as Modifier of Pathological Phenotype?" International Journal of Molecular Sciences 22, no. 1: 70. https://doi.org/10.3390/ijms22010070