Gene Variants Involved in Nonsense-Mediated mRNA Decay Suggest a Role in Autism Spectrum Disorder
Abstract
:1. Introduction
2. Materials and Methods
2.1. Identification of Genes Encoding NMD Factors and Regulators
2.2. ASD Genomic Datasets
2.3. Sequencing Data Processing, Annotation and SNV Discovery
2.4. CNV Discovery
2.5. Protein Domains
2.6. ASD Candidate Genes
2.7. Brain Expression of NMD Genes
3. Results
3.1. Genes Encoding Proteins Involved in the NMD Pathway
Evidence for NMD Involvement in ASD Pathophysiology
3.2. Discovery of SNVs in NMD Genes
3.2.1. EJC Components and Regulators
3.2.2. SURF and DECID Complexes
3.2.3. mRNA Decay
3.2.4. NMD Regulators
3.3. CNVs Encompassing NMD Genes in ASD Patients
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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NMD Group | Gene SYMBOL (1) | Alternative Name (2) | Role in NMD | References |
---|---|---|---|---|
EJC | EIF4A3 | eIF4AIII DDX48 | RNA helicase eukaryotic initiation factor 4A3 is a core EJC factor that interacts with the Y14-MAGOH heterodimer to provide a stable and direct binding site for the UPF3B protein and activate NMD | [45,46] |
RBM8A | Y14 | RNA-binding motif protein 8A is a core EJC factor that interacts with eIF4A3 and MAGOH to provide a stable and direct binding site for the UPF3B protein and activate NMD | [45,46] | |
MAGOH | MAGOH1 | Mago nashi homolog protein is a core EJC factor that interacts with eIF4A3 and Y14 to provide a stable and direct binding site for the UPF3B protein and activate NMD | [45,46,47] | |
MAGOHB | MGN2 | Mago nashi protein homolog B is a paralog of MAGOH that interacts with eIF4A3 and Y14 forming the trimeric EJC core to activate NMD | [47] | |
RNPS1 | RNA-binding protein S1 is a component of the SR-rich EJCs that enhances NMD in early phase of the pathway | [45,48] | ||
CASC3 | MLN51 BTZ | The peripheral EJC component CASC3 activates NMD and promotes SMG6-dependent endonucleolytic cleavage | [48,49,50] | |
ICE1 | KIAA0947 | Component of the little elongation complex promotes the association of EJC with UPF3B and activates NMD | [51] | |
PYM1 | WIGB | Ribosome-associated protein PYM interacts with Y14-MAGOH triggering EJC disassembly which leads to NMD inhibition | [52] | |
SURF-DECID | UPF1 | RENT1 smg-2 | Up-frameshift protein 1 is the central component of the NMD pathway; its helicase and ATPase activities are essential to trigger NMD | [46,53,54] |
UPF2 | RENT2 smg-3 | Up-frameshift protein 2 and UPF3B interact with UPF1 favoring its phosphorylation by SMG1 and formation of DECID complex | [46,53] | |
UPF3B | UPF3X | Up-frameshift protein 3B and UPF2 interact with UPF1 favoring its phosphorylation by SMG1 and formation of DECID complex; UPF3B also forms a stable trimeric complex with eRF1-eRF3a to promote dissociation of the termination complexes and triggers NMD | [46,53,54,55] | |
ETF1 | eRF1 | Eukaryotic release factor 1 is part of the eRF1–eRF3 translation termination complex that associates with UPF1 and SMG1-SMG8-SMG9 to form SURF and activate NMD | [53] | |
GSPT1 | eRF3a | Eukaryotic release factor 3 is part of the eRF1–eRF3 translation termination complex that associates with UPF1 and SMG1-SMG8-SMG9 to form SURF and activate NMD | [53] | |
NCBP1 | CBP80 | Component of the cap-binding complex (CBC) directly binds to UPF1, promoting the interaction with UPF2 to form SURF and activate NMD | [56,57,58] | |
NCBP2 | CBP20 | Component of the CBC is essential for the stability of complex | [56,57,58] | |
EIF4E | eIF4E | Eukaryotic translation initiation factor 4E binds to UPF1 and activates NMD | [59] | |
SMG1 | ATX | Suppressor of morphogenesis in genitalia-1 associate with SMG8-SMG9 to form the SMG1c kinase complex that catalyzes UPF1 phosphorylation | [53,60,61] | |
SMG8 | Suppressor of morphogenesis in genitalia-8 and suppressor of morphogenesis in genitalia-9 are co-factors that regulate SMG1 kinase activity | [53,60,61] | ||
SMG9 | ||||
DHX34 | KIAA0134 | RNA helicase DHX34 binds SMG1 and promotes UPF1 phosphorylation, triggering the conversion from the SURF to the DECID complex | [62,63,64] | |
RUVBL1 | RVB1 | AAA-ATPases RUVBL1 and RUVBL2 form a hetero-hexameric ring promoting the transition from SURF to the DECID complex | [65,66] | |
RUVBL2 | RVB2 | |||
mRNA decay | SMG5 | EST1B | Suppressor of morphogenesis in genitalia-5 and -7 form a heterodimer that binds p-UPF1 and recruit decapping enzymes, the CCR4-NOT complex (through CNOT8) and PP2A | [54,67,68] |
SMG7 | EST1C | |||
SMG6 | EST1A | Endonuclease that interacts both with UPF1 and p-UPF1 and cleaves NMD targets close to the PTC | [54,69,70,71] | |
CNOT8 | POP2 CAF1 | CCR4-NOT transcription complex subunit 8 is recruited by SMG7 to degrade NMD targets | [72] | |
DCP1A | mRNA-decapping enzyme 1A is a decapping activator and together with PNRC2 stimulate the decapping activity of DCP2 | [73] | ||
PNRC2 | Proline rich nuclear receptor coactivator 2 binds p-UPF1 and stimulate the decapping activity of DCP2 | [73] | ||
DCP2 | Decapping protein engaged in the 5′→3′ mRNA degradation | [74] | ||
MOV10 | gb110 | RNA helicase contributes to degradation of UPF1-regulated transcripts | [75] | |
PPP2CA | PP2AC | Protein phosphatase 2 (PP2A) promotes dephosphorylation of UPF1; both structural (PPP2R1A) and catalytic (PPP2CA) subunits of PP2A interact with SMG5 | [54,67,68] | |
PPP2R1A | PP2AA | |||
XRN1 | Exonuclease involved in 5′→3′ mRNA degradation | [74] | ||
DIS3L | DIS3L1 | Core exosome-associated factor involved in the 3′→5′ mRNA degradation | [76] | |
DIS3L2 | Exoribonuclease that degrades mRNA from 3′→5′ | [77] | ||
EXOSC10 | PM/Scl100 Rrp6p | Exosome catalytic subunit involved in the 3′→5′ mRNA degradation | [74] | |
PARN | Ribonuclease engaged in the 3′→5′ mRNA degradation | [74] | ||
ER–NMD | NBAS | NAG | Protein involved in Golgi-to-endoplasmic reticulum (ER) retrograde transport recruits UPF1 to the membrane of the ER and regulates a subset of NMD targets translated at the ER | [62,78] |
Regulator | PABPC1 | PABP1 | Polyadenylate-binding protein 1 inhibits the interaction of UPF1 with eRF3, repressing NMD | [79,80] |
EIF4G1 | EIF4G | Eukaryotic initiation factor 4G inhibits NMD | [81,82] | |
UPF3A | UPF3 | Up-frameshift protein 3A compete with UPF3B for UPF2-binding and inhibits NMD | [83] | |
FMR1 | FMRP | Fragile X mental retardation protein binds directly to UPF1 and acts as an NMD repressor | [28] | |
EIF3E | INT6 EIF3S6 | Eukaryotic translation initiation factor 3 subunit E is a non-core eIF3 subunit that interacts with UPF2 and triggers NMD | [84] | |
SRSF1 | SFRS1 | Serine/arginine-rich splicing factor 1 promotes NMD by enhancing UPF1-binding to the mRNA in the nucleus and it is also involved in UPF1 dephosphorylation | [85] | |
SEC13 | GNL2 and SEC13 are conserved NMD factors that regulate endogenous NMD targets but their exact role is unknown | [86] | ||
GNL2 | Ngp-1 |
NMD Group | Gene | Location | CNV Type | Gene Region | Protein Domains Affected | ASD N (1) |
---|---|---|---|---|---|---|
EJC | RBM8A | 1q21.1 | Deletion | Whole gene | All domains | 1 |
RBM8A | 1q21.1 | Duplication | Whole gene | All domains | 3 | |
SURF-DECID | UPF2 | 10p14 | Duplication | Partial | MIF4G domains | 1 |
UPF3B | Xq24 | Duplication | Whole gene | All domains | 1 | |
GSPT1 | 16p13.13 | Duplication | Whole gene | All domains | 1 | |
NCBP2 | 3q29 | Deletion | Whole gene | All domains | 1 | |
DHX34 | 19q13.32 | Deletion | Whole gene | All domains | 1 | |
RUVBL2 | 19q13.33 | Duplication | Partial | DI domain | 1 | |
mRNA decay | DIS3L | 15q22.31 | Duplication | Whole gene | All domains | 1 |
DIS3L2 | 2q37.1 | Deletion | Partial | Part of CSD2 and RNB domains | 1 | |
DIS3L2 | 2q37.1 | Duplication | Partial | RNB and C-terminal S1 domain | 1 | |
EXOSC10 | 1p36.22 | Deletion | Partial | PMC2NT, EXO1 and HRCD domains | 1 | |
EXOSC10 | 1p36.22 | Duplication | Partial | EXO and HRCD domain | 1 | |
MOV10 | 1p13.2 | Duplication | Whole gene | All domains | 2 | |
PARN | 16p13.12 | Deletion | Partial | All domains | 1 | |
PPP2R1A | 19q13.41 | Duplication | Partial | PP2A subunit B binding | 1 | |
SMG6 | 17p13.3 | Duplication | Partial | PIN domain | 1 | |
XRN1 | 3q23 | Duplication | Partial | XRN1 SH3-like domain | 13 | |
ER-NMD | NBAS | 2p24.3 | Duplication | Partial | Sec39-like domain | 1 |
Regulator | FMR1 | Xq27.3 | Deletion | Partial | KH2, NES and RGG domains | 1 |
UPF3A | 13q34 | Duplication | Whole gene | All domains | 2 | |
UPF3A | 13q34 | Duplication | Partial | EJC-binding domain | 1 |
NMD Group | Gene | Location | SNVs (1) | CNVs (1) | N ASD (2) | pLI | mis_Z | SFARI (3) | |
---|---|---|---|---|---|---|---|---|---|
LoF | MISPD | ||||||||
EJC | EIF4A3 | 17q25.3 | 1 | 1 | 1.00 | 4.02 | |||
RBM8A | 1q21.1 | 2 | 4 | 0.57 | 2.16 | 1q21.1 region | |||
CASC3 | 17q21.1 | 3 | 3 | 0.61 | 1.32 | ||||
ICE1 | 5p15.32 | 2 | 7 | 10 | 1.00 | 0.73 | |||
SURF-DECID | UPF1 | 19p13.11 | 4 | 4 | 1.00 | 5.63 | |||
UPF2 | 10p14 | 1 | 3 | 1 | 11 | 1.00 | 3.19 | category 3 | |
UPF3B | Xq24 | 1 | 3 | 1 | 7 | 0.98 | 1.84 | category 1 | |
ETF1 | 5q31.2 | 1 | 3 | 6 | 1.00 | 4.39 | |||
GSPT1 | 16p13.13 | 4 | 1 | 7 | 1.00 | 3.32 | |||
DHX34 | 19q13.32 | 2 | 12 | 1 | 25 | 0.00 | −0.08 | ||
RUVBL1 | 3q21.3 | 1 | 1 | 1.00 | 3.39 | ||||
RUVBL2 | 19q13.33 | 1 | 1 | 2 | 1.00 | 3.11 | |||
SMG1 | 16p12.3 | 1 | 12 | 13 | 1.00 | 3.30 | |||
SMG8 | 17q22 | 6 | 8 | 0.01 | 1.73 | ||||
SMG9 | 19q13.31 | 1 | 1 | 4 | 0.00 | 1.60 | |||
mRNA decay | SMG5 | 1q22 | 2 | 2 | 0.01 | 1.13 | |||
SMG6 | 17p13.3 | 2 | 1 | 6 | 0.98 | 0.18 | category 3 | ||
SMG7 | 1q25.3 | 8 | 14 | 1.00 | 2.19 | ||||
ER-NMD | NBAS(4) | 2p24.3 | 5 | 20 | 1 | 99 | 0.00 | −0.87 | |
Regulator | UPF3A | 13q34 | 1 | 2 | 2 | 11 | 0.00 | −0.60 | |
SRSF1 | 17q22 | 1 | 1 | 0.98 | 3.96 | ||||
SEC13(4) | 3p25.3 | 2 | 2 | 0.02 | 0.62 | ||||
GNL2(4) | 1p34.3 | 1 | 11 | 17 | 0.00 | 0.28 |
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Marques, A.R.; Santos, J.X.; Martiniano, H.; Vilela, J.; Rasga, C.; Romão, L.; Vicente, A.M. Gene Variants Involved in Nonsense-Mediated mRNA Decay Suggest a Role in Autism Spectrum Disorder. Biomedicines 2022, 10, 665. https://doi.org/10.3390/biomedicines10030665
Marques AR, Santos JX, Martiniano H, Vilela J, Rasga C, Romão L, Vicente AM. Gene Variants Involved in Nonsense-Mediated mRNA Decay Suggest a Role in Autism Spectrum Disorder. Biomedicines. 2022; 10(3):665. https://doi.org/10.3390/biomedicines10030665
Chicago/Turabian StyleMarques, Ana Rita, João Xavier Santos, Hugo Martiniano, Joana Vilela, Célia Rasga, Luísa Romão, and Astrid Moura Vicente. 2022. "Gene Variants Involved in Nonsense-Mediated mRNA Decay Suggest a Role in Autism Spectrum Disorder" Biomedicines 10, no. 3: 665. https://doi.org/10.3390/biomedicines10030665
APA StyleMarques, A. R., Santos, J. X., Martiniano, H., Vilela, J., Rasga, C., Romão, L., & Vicente, A. M. (2022). Gene Variants Involved in Nonsense-Mediated mRNA Decay Suggest a Role in Autism Spectrum Disorder. Biomedicines, 10(3), 665. https://doi.org/10.3390/biomedicines10030665