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Research Paper
Open Access

RGS3 and IL1RAPL1 missense variants implicate defective neurotransmission in early-onset inherited schizophrenias

Ambreen Kanwal, José V. Pardo and Sadaf Naz
J Psychiatry Neurosci November 01, 2022 47 (6) E379-E390; DOI: https://doi.org/10.1503/jpn.220070
Ambreen Kanwal
From the School of Biological Sciences, University of the Punjab, Lahore, Pakistan (Kanwal, Naz); the Department of Psychiatry, University of Minnesota, Minneapolis, Minn., USA (Pardo); the Minneapolis Veterans Affairs Health Care System, Minneapolis, Minn., USA (Pardo)
MS
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José V. Pardo
From the School of Biological Sciences, University of the Punjab, Lahore, Pakistan (Kanwal, Naz); the Department of Psychiatry, University of Minnesota, Minneapolis, Minn., USA (Pardo); the Minneapolis Veterans Affairs Health Care System, Minneapolis, Minn., USA (Pardo)
MD, PhD
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Sadaf Naz
From the School of Biological Sciences, University of the Punjab, Lahore, Pakistan (Kanwal, Naz); the Department of Psychiatry, University of Minnesota, Minneapolis, Minn., USA (Pardo); the Minneapolis Veterans Affairs Health Care System, Minneapolis, Minn., USA (Pardo)
PhD
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  • Figure 1
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    Figure 1

    Pedigrees of families PSYAK2 and PSYAK3 with variant segregation and conservation. Asterisks depict individuals who participated in the study. Filled symbols indicate affected individuals. Double lines show consanguineous marriages. (A) Family PSYAK2. Six individuals participated in the study. (B) Family PSYAK3. Five individuals participated in the study. (C) Partial chromatograms of RGS3 for an unaffected wild-type individual, a heterozygous carrier and a homozygous affected individual. The arrow indicates the point of the variant. (D) Partial chromatograms of IL1RAPL1. Affected individuals were hemizygous, whereas their mother was a heterozygous carrier. The unaffected brother and the father were hemizygous for the wild-type allele. (E) Multiple sequence alignment of RGS3 from diverse vertebrates showing p.Arg217 conservation (highlighted). (F) Multiple sequence alignment of IL1RAPL1 from diverse vertebrates showing p.Thr234 conservation (highlighted).

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    Figure 2:

    Schematic representation of RGS3 isoforms, domains and encoded protein. Asterisks depict the position of the variant detected in family PSYAK2. Longer mRNA transcripts encode proteins that are predicted to localize to the cytosol or associate with the plasma membrane. Shorter, N-terminally truncated forms may be nuclear. Black boxes indicate noncoding exons. (A) RGS3 isoform NM_144488.8 encodes the protein with the highest molecular weight, consisting of 1198 amino acids. (B) RGS3 isoform NM_001282923.2 contains 22 exons with the variant c.649C > T within exon 4. (C) RGS3 isoform NM_17790.6 encodes a truncated protein. (D) RGS3 isoform NM_1276261.2 lacks exons encoding plasma membrane or cytoplasmic domains. (E) RGS3 isoform NM_1276260.2 encodes a protein that is N-terminally truncated. (F) RGS3 isoform NM_144490.4 is the shortest isoform. (G) Schematic representation of RGS3 isoform NP_652759.4 showing different domains. The c.649C > T, p.(Arg217Cys) variant is within the C2 domain, which is involved in Ca+2-dependent translocation of the RGS3 protein. (H) RGS3 inhibits the G-protein-mediated postreceptor signalling pathway. The C2 domain at the N-terminal translocates RGS3 from the cytosol to the plasma membrane, whereas the PDZ domain interacts with neuroligin and AMPAR GluR2, which further binds with EphrinB2. After translocation to the plasma membrane, the RGS domain of RGS3 interacts with the heterotrimeric G-proteins, which are composed of α, β and γ subunits. G-protein-coupled receptors activate guanylyl cyclase, which converts GMP to cGMP. It activates adenylyl cyclase to convert cAMP to AMP and activates multiple cytoplasmic proteins, including PED1C. The ligand binds with the ET-1 receptor and activates MAP kinase via cleavage of PIP2 to IP3 (left side). IP3 induces the uptake of Ca+2 through protein kinase C. PED1C inhibits protein kinase C and reduces intracellular Ca+2 by deterring the ET-1 signalling pathway. AMP = adenosine monophosphate; AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; cAMP = cyclic AMP; cGMP = cyclic GMP; ET-1 = endothelin-1; GAP = GTPase activating protein; GDP = guanosine diphosphate; GEF = guanidine exchange factor; GMP = guanosine monophosphate; GTP = guanosine triphosphate; IP3 = inositol triphosphate; MAP = mitogen-activated protein; PDE1C = calmodulin dependent cyclic nucleotide phosphodiesterase; PIP2 = phosphatidylinositol 4,5-bisphosphate.

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    Figure 3

    Schematic representation of IL1RAPL1 isoforms, domains and encoded protein. (A) IL1RAPL1 isoform NM_014271.4 has 11 exons encoding a 696 amino acid protein. An asterisk marks the position of the variant c.700A > G, p.(Thr234Ala), detected in family PSYAK3. (B) Schematic representation of multiple domains in IL1RAPL1, including the N-terminal signal peptide, 3 extracellular Ig-like domains, a TM region, a TIR domain and a C-terminal tail with a PDZ binding domain. (C) At the presynaptic terminal, Ig domains of PTP-δ interact with Ig domains of IL1RAPL1 and increase excitation across the synaptic cleft. The TIR domain interacts with RhoGAP2, with the help of NCS-1 calcium channels. RhoGAP2 is involved in GTPase intrinsic activity and regulates a number of neuronal signalling pathways. The PDZ binding motif of IL1RAPL1 interacts with the PDZ domain of PSD-95 by Ser-295 and regulates the synaptic localization of PSD-95. The C-terminal PDZ binding domain of IL1RAPL1 phosphorylates JNK by MEKK. JNK phosphorylation activates PSD-95 and induces maturation of the synapse. GTPase = guanosine triphosphatase; Ig = immunoglobulin; JNK = C-Jun terminal kinase; MAP = mitogen-activated protein; MEKK = MAP kinase kinase; NCS-1 = neuronal calcium sensor-1; PSD-95 = postsynaptic scaffolding protein-95; PTP-δ = protein tyrosine phosphatase δ; RhoGAP2 = Rho GTPase-activating protein 2; TIR = toll/interleukin-1R; TM = transmembrane.

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    Figure 4

    Structural modelling of wild-type and mutant RGS3 and IL1RAPL1 proteins. (A) Structural models of wild-type RGS3 protein (upper panel) and IL1RAPL1 protein (lower panel). (B) Interacting bonds of wild-type RGS3 p.Arg217 and IL1RAPL1 p.Thr234 proteins. (C) RGS3 p.(Arg217Cys) and IL1RAPL1 p.(Thr234Ala) variants. The RGS3 variant cysteine is in the exposed region of the protein, making it highly accessible to solvent molecules. The IL1RAPL1 variant alanine is in a buried region of the protein and may not directly affect the interaction of the protein.

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    Table 1

    Filtered variants for families PSYAK2 and PSYAK3 after exome sequencing

    Aggregated allele frequency, %Predictions
    Family IDGenegDNA change*RefSeq IDcDNA change and amino acid changegnomADFrom 300 ethnically matched controls†Conservation GERP‡CADDSIFTPolyPhen2REVELMTFATHMMSpliceAl
    PSYAK2OR13C2Chr9: 107367821
    G > C
    NM_001004481.1c.88C > G p.Leu30Val, missense0.0002781 (0 homozygous)0.001671.458.1290.09
    T
    0.03
    B
    0
    B
    0.03
    B
    2.32
    T
    0.03
    B
    RGS3Chr9: 116247933
    C > T
    NM_144488.5c.649C > T p.Arg217Cys, missense0.00004903 (0 homozygous)04.66320
    D
    1
    D
    0.62
    D
    0.99
    D
    −1.07
    B
    0.13
    U
    NR6A1Chr9: 127287141 G > ANM_033334.4c.1213C > T p.Leu405Leu, synonymous0.0006331 (0 homozygous)0NA11.49NANANANANANA
    GAPVD1Chr9: 128117939 C > TNM_001282680.2c.3774C > T p.Thr1258Thr, synonymous0.0001516 (0 homozygous)0.00167NA8.623NANANANANANA
    HMCN2Chr9: 133224403 C > TNM_001291815.2c.2514C > T p.Asp838Asp, synonymous0.0014 (1 homozygous)0.01NA0.231NANANANANANA
    MED27Chr9: 134735938
    G > A
    NM_004269.4c.923C > T p.Thr308Ile, missense0.0002064 (1 homozygous)05.323.30.06
    T
    0.11
    B
    0.24
    B
    1
    D
    NA0
    B
    SETXChr9: 135202835
    A > T
    NM_015046.7c.4150T > A p.Ser1384Thr, missense0.0001352 (0 homozygous)0.00167−0.186.7140.02
    D
    0.09
    B
    0.27
    B
    0
    B
    −2.19
    D
    0
    B
    FLI1§Chr11: 128651917 A > GNM_002017.5c.654 A > G
    p.Glu218Glu, synonymous
    0.0002607
    (1 homozygous)
    0.002NA21.1NANANANANA0.01
    D
    SNX19Chr11: 130749601
    C > T
    NM_014758.2c.2764G > A p.Val922Ile, missense0.00001593 (0 homozygous)0−2.380.1270.46
    T
    0.05
    B
    0.02
    B
    0
    B
    1.55
    T
    0
    B
    PSYAK3WDR33Chr2: 128477570
    T > C
    NM_018383.5c.2029A > G p.Met677Val, missense0.0001316 (0 homozygous)0.0067−0.1418.220.06
    T
    NA0.1
    B
    0.66
    D
    2.55
    T
    0
    B
    CD44Chr11: 35160895 G > CNM_000610.3c.45G > C p.Val15Val, synonymous0.0008269 (2 homozygous)0.01NA14.61NANANANANANA
    STX3Chr 11: 59557993
    C > T
    NM_004177.5c.291C > T p.Ser97Ser, synonymous0.001515 (2 homozygous)0.015NA14.77NANANANANA0
    B
    ROM1Chr11: 62380834 G > TNM_000327.3c.81G > T p.Leu27Leu, synonymous0.001259 (0 homozygous)0.0033NA0.699NANANANANANA
    C11ORF95Chr11: 63531586 G > ANM_001144936.2c.1509C > T p.Pro503Pro, synonymous0.0008351 (0 homozygous)0.005NA5.782NANANANANANA
    TRIM64BChr11: 89608155 A > GNM_001164397.2c.495T > C p.His165His, synonymous0.0002230 (0 homozygous)0.00167NA0.325NANANANANANA
    IL1RAPL1ChrX: 29417422
    A > G
    NM_014271.3c.700A > G p.Thr234Ala, missense0.000005491 (1 hemizygous)05.7523.80.08
    T
    NA0.52
    D
    1
    D
    −1.07
    T
    0
    B
    • B = benign; CADD = Combined Annotation Dependent Depletion (higher scores are more damaging); D = damaging or deleterious; GERP = Genomic Evolutionary Rate Prediction; gnomAD = Genome Aggregation Database; FATHMM = Functional Annotation Through Hidden Markov Models; MT = Mutation Taster; NA = not applicable; PolyPhen2 = Polymorphism Phenotyping v2; RefSeq = Reference Sequence; REVEL = Rare Exome Variant Ensemble Learner; SIFT = Sorting Intolerant from Tolerant algorithm; SpliceAI = Splice Altering algorithm; T = tolerated; U = uncertain.

    • ↵* Variant position according to Human Feb.2009 (GRCh37/hg19) Assembly.

    • ↵† RGS3 and IL1RAPL1 variants were absent from the in-house exome data of at least 300 ethnically matched controls and from the DNA of a further 100 individuals analyzed.

    • ↵‡ Negative and low scores indicate no or low conservation.

    • ↵§ In family PSYAK2, the FLI1 synonymous variant was predicted to affect splicing. However, the involved nucleotide was not conserved in evolution and had an allele frequency of 0.002 in South Asians, making it unlikely that it would be pathogenic.

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Journal of Psychiatry and Neuroscience: 47 (6)
J Psychiatry Neurosci
Vol. 47, Issue 6
20 Dec 2022
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RGS3 and IL1RAPL1 missense variants implicate defective neurotransmission in early-onset inherited schizophrenias
Ambreen Kanwal, José V. Pardo, Sadaf Naz
J Psychiatry Neurosci Nov 2022, 47 (6) E379-E390; DOI: 10.1503/jpn.220070

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RGS3 and IL1RAPL1 missense variants implicate defective neurotransmission in early-onset inherited schizophrenias
Ambreen Kanwal, José V. Pardo, Sadaf Naz
J Psychiatry Neurosci Nov 2022, 47 (6) E379-E390; DOI: 10.1503/jpn.220070
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