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Functional classification of GNAI1 disorder variants in C. elegans uncovers conserved and cell-specific mechanisms of dysfunction

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Salama, Rehab, Peet, Eric, Morrione, Logan, Durant, Sarah, Seager, Maxwell, Rennie, Madison, Scarlata, Suzanne, Nechipurenko, Inna·2025·Genetics
DOI 10.1101/2025.08.18.670960PMC PMC12693566

Preprint — published as 10.1093/genetics/iyaf216 · Paper page

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Abstract

Heterotrimeric G proteins transduce signals from G protein coupled receptors, which mediate key aspects of neuronal development and function. Mutations in the GNAI1 gene, which encodes Gαi1, cause a disorder characterized by developmental delay, intellectual disability, hypotonia, and epilepsy. However, the mechanistic basis for this disorder remains unknown. Here, we show that GNAI1 is required for ciliogenesis in human cells and use C. elegans as a whole-organism model to determine the functional impact of seven GNAI1 -disorder patient variants. Using CRISPR-Cas9 editing in combination with robust cellular (cilia morphology) and behavioral (chemotaxis) assays, we find that T48I , K272R , A328P , and V334E orthologous variants impact both cilia assembly and function in AWC neurons, M88V and I321T have no impact on either phenotype, and D175V exerts neuron-specific effects on cilia-dependent sensory behaviors. Finally, we validate in human ciliated cell lines that D173V , K270R , and A326P GNAI1 variants disrupt ciliary localization of the encoded human Gαi1 proteins similarly to their corresponding orthologous substitutions in the C. elegans ODR-3 (D175V , K272R , and A328P ). Overall, our findings determine the in vivo effects of orthologous GNAI1 variants and contribute to mechanistic understanding of GNAI1 disorder pathogenesis as well as neuron-specific roles of ODR-3 in sensory biology. ARTICLE SUMMARY: Gα subunits of heterotrimeric G proteins transduce signaling from G protein coupled receptors and play important roles in cell communication and complex behaviors. Mutations in the GNAI1 gene, which encodes Gαi1 protein, have been recently linked to a neurodevelopmental disorder; however, it remains unknown how GNAI1 patient mutations disrupt neuronal development or function to manifest in disease. We demonstrate that GNAI1 is required for ciliogenesis and use C. elegans as a whole-animal model in combination with human cells to identify cell-specific and conserved mechanisms of Gα dysfunction.

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Fig. 1. GNAI1 knockdown impairs ciliogenesis in human cells. a, b) Immunofluorescence images of fixed a) RPE-1 and b) HEK293T cells transfected with the indicated siRNAs. Arrowheads mark cilia labeled with anti-ARL13B antibody. Scale: 10 μm. c, d) Quantification of ciliation in c) RPE-1 and d) HEK293T cells transfected with the indicated siRNAs. Each data point represents 1 replicate. Total number of cells: siControl (n = 858 RPE-1, n = 4,460 HEK293T), siGNAI1 #1 (n = 518 RPE-1, n = 4,600 HEK293T), siGNAI1 #2 (n = 400). Means ± SD are indicated by shaded and vertical bars, respectively. ***Different from control at P < 0.001 (Fisher's exact test). e) Relative levels of GNAI1 mRNA in RPE-1 and HEK293T cells treated with the indicated siRNAs. Summary data represent 4 replicates per condition per cell type. Error bars are SEM. *Different from control at P < 0.05 (Mann–Whitney test).
Fig. 1. GNAI1 knockdown impairs ciliogenesis in human cells. a, b) Immunofluorescence images of fixed a) RPE-1 and b) HEK293T cells transfected with the indicated siRNAs. Arrowheads mark cilia labeled with anti-ARL13B antibody. Scale: 10 μm. c, d) Quantification of ciliation in c) RPE-1 and d) HEK293T cells transfected with the indicated siRNAs. Each data point represents 1 replicate. Total number of cells: siControl (n = 858 RPE-1, n = 4,460 HEK293T), siGNAI1 #1 (n = 518 RPE-1, n = 4,600 HEK293T), siGNAI1 #2 (n = 400). Means ± SD are indicated by shaded and vertical bars, respectively. ***Different from control at P < 0.001 (Fisher's exact test). e) Relative levels of GNAI1 mRNA in RPE-1 and HEK293T cells treated with the indicated siRNAs. Summary data represent 4 replicates per condition per cell type. Error bars are SEM. *Different from control at P < 0.05 (Mann–Whitney test).CC BY · PubMed Central
Fig. 2. Distribution of patient variants selected for analysis. a) Left: 3D structure of Gαi1 bound to GDP (PDB accession: 2G83) (Johnston et al. 2006). Carbon, oxygen, nitrogen, and phosphorous atoms of GDP are shown as green, red, blue, and orange spheres, respectively. Right: AlphaFold-predicted structure of C. elegans ODR-3 (Varadi et al. 2022, 2024). Positions of missense patient variants that were selected for analysis are shown in magenta in both protein models. The protein structures for Gαi1 and ODR-3 were generated in the PyMOL Molecular Graphics System, Version 3.1.4 (Schrodinger, LLC). b) Schematic of human Gαi1 showing positions of GNAI1-disorder-associated variants (pins). Guanine nucleotide-binding motifs (G1 to G5 boxes) are shown in red. The Gαi1 protein diagram was generated using IBS 2.0 (Xie et al. 2022).
Fig. 2. Distribution of patient variants selected for analysis. a) Left: 3D structure of Gαi1 bound to GDP (PDB accession: 2G83) (Johnston et al. 2006). Carbon, oxygen, nitrogen, and phosphorous atoms of GDP are shown as green, red, blue, and orange spheres, respectively. Right: AlphaFold-predicted structure of C. elegans ODR-3 (Varadi et al. 2022, 2024). Positions of missense patient variants that were selected for analysis are shown in magenta in both protein models. The protein structures for Gαi1 and ODR-3 were generated in the PyMOL Molecular Graphics System, Version 3.1.4 (Schrodinger, LLC). b) Schematic of human Gαi1 showing positions of GNAI1-disorder-associated variants (pins). Guanine nucleotide-binding motifs (G1 to G5 boxes) are shown in red. The Gαi1 protein diagram was generated using IBS 2.0 (Xie et al. 2022).CC BY · PubMed Central
Fig. 3. Orthologous patient mutations in the odr-3 gene differentially affect subcellular localization of the encoded proteins. a) Diagram of the AWC olfactory neuron in the worm nose (only 1 AWC of a pair is shown for simplicity). The region inside of the dashed box is magnified in a panel on the left. TZ, transition zone; PCMC, periciliary membrane compartment. b) Representative images and cartoon summaries (bottom rows) showing localization of the indicated TagRFP-tagged ODR-3 variants in AWC neurons. AWC neurons were visualized via expression of ceh-36p::GFP, which also labels ASE neurons (arrows). Arrowheads mark cilia base/TZ. d, dendrite. Anterior is at the left. Scale: 5 μm. c) Quantification of relative TagRFP fluorescence inside the AWC cilium vs distal dendrite for the indicated TagRFP-tagged ODR-3 variants. Total number of AWC neurons analyzed for each variant: WT (n = 27), T48I (n = 42), M88V (n = 26), D175V (n = 22), K272R (n = 21), I321T (n = 26), A328P (n = 28), and V334E (n = 29). Means ± SD are indicated by horizontal and vertical bars, respectively. ***Different from WT at P < 0.001 (Kruskal–Wallis with Dunn's multiple comparisons test).
Fig. 3. Orthologous patient mutations in the odr-3 gene differentially affect subcellular localization of the encoded proteins. a) Diagram of the AWC olfactory neuron in the worm nose (only 1 AWC of a pair is shown for simplicity). The region inside of the dashed box is magnified in a panel on the left. TZ, transition zone; PCMC, periciliary membrane compartment. b) Representative images and cartoon summaries (bottom rows) showing localization of the indicated TagRFP-tagged ODR-3 variants in AWC neurons. AWC neurons were visualized via expression of ceh-36p::GFP, which also labels ASE neurons (arrows). Arrowheads mark cilia base/TZ. d, dendrite. Anterior is at the left. Scale: 5 μm. c) Quantification of relative TagRFP fluorescence inside the AWC cilium vs distal dendrite for the indicated TagRFP-tagged ODR-3 variants. Total number of AWC neurons analyzed for each variant: WT (n = 27), T48I (n = 42), M88V (n = 26), D175V (n = 22), K272R (n = 21), I321T (n = 26), A328P (n = 28), and V334E (n = 29). Means ± SD are indicated by horizontal and vertical bars, respectively. ***Different from WT at P < 0.001 (Kruskal–Wallis with Dunn's multiple comparisons test).CC BY · PubMed Central
Fig. 4. Intraciliary localization of A328P ODR-3 variant is increased in mks-5 mutants. a, b) Representative images (top and middle) and cartoons (bottom) showing localization of TagRFP-tagged ODR-3WT and ODR-3A328P proteins in AWC cilia of a) wild-type animals and b) mks-5(tm3100) mutants. AWC neurons were visualized via expression of ceh-36p::GFP, which also labels ASE neurons (arrows). Arrowheads mark cilia base/TZ. cil., cilium; dendr., dendrite. Anterior is at the left. Scale: 5 μm. c) Quantification of relative TagRFP fluorescence inside the AWC cilium vs distal dendrite for the indicated TagRFP-tagged ODR-3 variants in wild-type and mks-5(tm3100) mutant animals. Total number of AWC neurons analyzed for each variant: wild type (n = 16 ODR-3WT, n = 28 ODR-3A328P), mks-5(tm3100) (n = 17 ODR-3WT, n = 18 ODR-3A328P). Data for ODR-3WT localization in the wild-type background are repeated from Fig. 3c. Means ± SD are indicated by horizontal and vertical bars, respectively. *** and ###Different between bracketed groups at P < 0.001 (Kruskal–Wallis with Dunn's multiple comparisons test).
Fig. 4. Intraciliary localization of A328P ODR-3 variant is increased in mks-5 mutants. a, b) Representative images (top and middle) and cartoons (bottom) showing localization of TagRFP-tagged ODR-3WT and ODR-3A328P proteins in AWC cilia of a) wild-type animals and b) mks-5(tm3100) mutants. AWC neurons were visualized via expression of ceh-36p::GFP, which also labels ASE neurons (arrows). Arrowheads mark cilia base/TZ. cil., cilium; dendr., dendrite. Anterior is at the left. Scale: 5 μm. c) Quantification of relative TagRFP fluorescence inside the AWC cilium vs distal dendrite for the indicated TagRFP-tagged ODR-3 variants in wild-type and mks-5(tm3100) mutant animals. Total number of AWC neurons analyzed for each variant: wild type (n = 16 ODR-3WT, n = 28 ODR-3A328P), mks-5(tm3100) (n = 17 ODR-3WT, n = 18 ODR-3A328P). Data for ODR-3WT localization in the wild-type background are repeated from Fig. 3c. Means ± SD are indicated by horizontal and vertical bars, respectively. *** and ###Different between bracketed groups at P < 0.001 (Kruskal–Wallis with Dunn's multiple comparisons test).CC BY · PubMed Central
Fig. 5. Orthologous patient mutations in the odr-3 gene differentially alter AWC cilia morphology and function. a) Representative images of AWC cilia in animals homozygous for the indicated odr-3 mutations and odr-3(lf) animals overexpressing the odr-3K272R transgene. AWC neurons were visualized via expression of ceh-36p::GFP, which also labels ASE neurons (arrows). Arrowheads mark cilia base/TZ. Anterior is at the left. Scale: 5 μm. b) Quantification of AWC cilia size in the indicated genotypes. Total number of cilia: WT (n = 34), odr-3(lf) (n = 15), T48I (n = 31), M88V (n = 40), D175V (n = 59), K272R (n = 45), I321T (n = 41), A328P (n = 32), A328P rescue (n = 32), and V334E (n = 29). Means ± SD are indicated by shaded and vertical bars, respectively. *, **, and ***Different from WT at P < 0.05, 0.01, and 0.001, respectively (Kruskal–Wallis with Dunn's multiple comparisons test). ###Different between bracketed genotypes at P < 0.001 (unpaired t test with Welch's correction). c) Schematic of chemotaxis assay. d) Chemotaxis responses of the indicated homozygous variants. Individual data points represent chemotaxis index from 1 assay. Total number of assays: WT (n = 50), odr-3(lf) (n = 43), T48I (n = 8), M88V (n = 6), D175V (n = 10), I321T (n = 4), A328P (n = 13), A328P rescue (n = 16), and V334E (n = 25). Means ± SD are indicated by shaded and vertical bars, respectively. * and ***Different from wild type at P < 0.05 and 0.001, respectively (Kruskal–Wallis with Dunn's multiple comparisons test). ###Different between bracketed genotypes at P < 0.001 (unpaired t test with Welch's correction). e) Chemotaxis responses of wild-type, odr-3(lf), and odr-3(lf) mutants overexpressing odr-3K272R transgene in AWC neurons. Individual data points represent chemotaxis index from 1 assay. Total number of assays: WT (n = 10), odr-3(lf) (n = 10), and odr-3(lf); K272 OE (n = 10). Means ± SD are indicated by shaded and vertical bars, respectively. ** and ***Different from wild type at P < 0.01 and 0.001, respectively (Kruskal–Wallis with Dunn's multiple comparisons test).
Fig. 5. Orthologous patient mutations in the odr-3 gene differentially alter AWC cilia morphology and function. a) Representative images of AWC cilia in animals homozygous for the indicated odr-3 mutations and odr-3(lf) animals overexpressing the odr-3K272R transgene. AWC neurons were visualized via expression of ceh-36p::GFP, which also labels ASE neurons (arrows). Arrowheads mark cilia base/TZ. Anterior is at the left. Scale: 5 μm. b) Quantification of AWC cilia size in the indicated genotypes. Total number of cilia: WT (n = 34), odr-3(lf) (n = 15), T48I (n = 31), M88V (n = 40), D175V (n = 59), K272R (n = 45), I321T (n = 41), A328P (n = 32), A328P rescue (n = 32), and V334E (n = 29). Means ± SD are indicated by shaded and vertical bars, respectively. *, **, and ***Different from WT at P < 0.05, 0.01, and 0.001, respectively (Kruskal–Wallis with Dunn's multiple comparisons test). ###Different between bracketed genotypes at P < 0.001 (unpaired t test with Welch's correction). c) Schematic of chemotaxis assay. d) Chemotaxis responses of the indicated homozygous variants. Individual data points represent chemotaxis index from 1 assay. Total number of assays: WT (n = 50), odr-3(lf) (n = 43), T48I (n = 8), M88V (n = 6), D175V (n = 10), I321T (n = 4), A328P (n = 13), A328P rescue (n = 16), and V334E (n = 25). Means ± SD are indicated by shaded and vertical bars, respectively. * and ***Different from wild type at P < 0.05 and 0.001, respectively (Kruskal–Wallis with Dunn's multiple comparisons test). ###Different between bracketed genotypes at P < 0.001 (unpaired t test with Welch's correction). e) Chemotaxis responses of wild-type, odr-3(lf), and odr-3(lf) mutants overexpressing odr-3K272R transgene in AWC neurons. Individual data points represent chemotaxis index from 1 assay. Total number of assays: WT (n = 10), odr-3(lf) (n = 10), and odr-3(lf); K272 OE (n = 10). Means ± SD are indicated by shaded and vertical bars, respectively. ** and ***Different from wild type at P < 0.01 and 0.001, respectively (Kruskal–Wallis with Dunn's multiple comparisons test).CC BY · PubMed Central
Fig. 6. The D175V variant disrupts ODR-3 localization to the ASH cilia and impairs ASH-mediated behavior. a) Schematic of the amphid channel. Only AWC and ASH cilia are shown for simplicity. Socket and sheath are glial cells that form the channel. Anterior is up. b) Representative images showing localization of TagRFP-tagged WT and D175V variants of ODR-3 in ASH and ASI neurons. ASH and ASI neurons were visualized via expression of sra-6p::GFP. Arrowheads mark cilia base/TZ. Anterior is at the left. Scale: 5 μm. c) Quantification of relative TagRFP fluorescence inside the ASH cilium vs distal dendrite for the indicated TagRFP-tagged ODR-3 variants. Total number of ASH neurons analyzed for each variant: WT (n = 32), D175V (n = 65). ***Different from WT at P < 0.001 (Mann–Whitney test). d) Diagram of glycerol avoidance assay. e) Fraction of animals that remain inside of an 8M-glycerol ring after 2 min (osmotic avoidance index). Genotypes of assayed animals are indicated. Each data point represents a mean osmotic index per genotype per day. Three to 8 technical replicates were assayed per genotype per day. Total number of assayed animals: WT (n = 298), odr-3(lf) (n = 264), D175V (n = 224), D175 rescue (n = 157). Means ± SD are indicated by shaded and vertical bars, respectively. ** and ***Different from wild type at P < 0.01 and 0.001, respectively (Fisher's exact test). ###Different between bracketed genotypes (Fisher's exact test).
Fig. 6. The D175V variant disrupts ODR-3 localization to the ASH cilia and impairs ASH-mediated behavior. a) Schematic of the amphid channel. Only AWC and ASH cilia are shown for simplicity. Socket and sheath are glial cells that form the channel. Anterior is up. b) Representative images showing localization of TagRFP-tagged WT and D175V variants of ODR-3 in ASH and ASI neurons. ASH and ASI neurons were visualized via expression of sra-6p::GFP. Arrowheads mark cilia base/TZ. Anterior is at the left. Scale: 5 μm. c) Quantification of relative TagRFP fluorescence inside the ASH cilium vs distal dendrite for the indicated TagRFP-tagged ODR-3 variants. Total number of ASH neurons analyzed for each variant: WT (n = 32), D175V (n = 65). ***Different from WT at P < 0.001 (Mann–Whitney test). d) Diagram of glycerol avoidance assay. e) Fraction of animals that remain inside of an 8M-glycerol ring after 2 min (osmotic avoidance index). Genotypes of assayed animals are indicated. Each data point represents a mean osmotic index per genotype per day. Three to 8 technical replicates were assayed per genotype per day. Total number of assayed animals: WT (n = 298), odr-3(lf) (n = 264), D175V (n = 224), D175 rescue (n = 157). Means ± SD are indicated by shaded and vertical bars, respectively. ** and ***Different from wild type at P < 0.01 and 0.001, respectively (Fisher's exact test). ###Different between bracketed genotypes (Fisher's exact test).CC BY · PubMed Central
Fig. 7. The D173V, K270R, and A326P variants in GNAI1 impair cilia localization of the encoded proteins in human cells. a) Immunofluorescence images of fixed HEK293T cells transfected with the indicated eGFP-tagged Gαi1 variants. Arrowheads mark cilia labeled with anti-ARL13B antibody. DAPI and anti-GOLGA2 label DNA and Golgi, respectively. Scale: 5 μm. b) Quantification of relative eGFP fluorescence in cilium vs Golgi for the indicated eGFP-tagged Gαi1 variants. Individual biological replicates for each variant are shown in different shades of the corresponding color. Diamonds: means of individual biological replicates. Total mean ± SD across all biological replicates is indicated by horizontal and vertical bars, respectively. Total number of cells analyzed for each Gαi1 variant: WT (n = 322), D173V (n = 220), K270R (n = 260), A326P (n = 315). ***Different from Gαi1WT at P < 0.001 (Kruskal–Wallis with Dunn's multiple comparisons test). c) Graphical summary of localization patterns for the indicated ODR-3 and Gαi1 variants in C. elegans (AWC and ASH neurons) and mammalian cells, respectively. TZ, transition zone.
Fig. 7. The D173V, K270R, and A326P variants in GNAI1 impair cilia localization of the encoded proteins in human cells. a) Immunofluorescence images of fixed HEK293T cells transfected with the indicated eGFP-tagged Gαi1 variants. Arrowheads mark cilia labeled with anti-ARL13B antibody. DAPI and anti-GOLGA2 label DNA and Golgi, respectively. Scale: 5 μm. b) Quantification of relative eGFP fluorescence in cilium vs Golgi for the indicated eGFP-tagged Gαi1 variants. Individual biological replicates for each variant are shown in different shades of the corresponding color. Diamonds: means of individual biological replicates. Total mean ± SD across all biological replicates is indicated by horizontal and vertical bars, respectively. Total number of cells analyzed for each Gαi1 variant: WT (n = 322), D173V (n = 220), K270R (n = 260), A326P (n = 315). ***Different from Gαi1WT at P < 0.001 (Kruskal–Wallis with Dunn's multiple comparisons test). c) Graphical summary of localization patterns for the indicated ODR-3 and Gαi1 variants in C. elegans (AWC and ASH neurons) and mammalian cells, respectively. TZ, transition zone.CC BY · PubMed Central

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Metadata

Authors
Salama, R., Peet, E., Morrione, L., Durant, S., Seager, M., Rennie, M., Scarlata, S., & Nechipurenko, I.
Affiliations
Worcester Polytechnic Institute (US)
Corresponding author
Nechipurenko, Inna
ORCID
Venue
Genetics
Publisher
openRxiv
Published
2025-08-22
Volume
231
Issue
4
ISSN
0016-6731 (ISSN-L)
DOI
10.1101/2025.08.18.670960
PMC
PMC12693566
OpenAlex
W4414867018
Cited by
2
References
81
Citations by year
2026: 1 · 2025: 1
FWCI
1.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Genetics (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • Charles H. Hood Foundation
  • National Institutes of Health (1r35gm155316-01, OD010440, P40OD010440)
  • National Institute of General Medical Sciences (R35 GM155316)
  • Office of Research Infrastructure Programs, National Institutes of Health (P40OD010440)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
GNAI1, Gαi1, heterotrimeric G proteins, intellectual disability, developmental delay, epilepsy, ciliogenesis, primary cilia, AWC neurons, odr-3, Caenorhabditis elegans, chemotaxis, sensory neurons, ciliary localization

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Salama, R., Peet, E., Morrione, L., Durant, S., Seager, M., Rennie, M., Scarlata, S., & Nechipurenko, I. (2025). Functional classification of GNAI1 disorder variants in C. elegans uncovers conserved and cell-specific mechanisms of dysfunction. Genetics. https://doi.org/10.1101/2025.08.18.670960