Undisclosed GPR161 modulator therapeutic / Omeros - LARVOL DELTA

Determining the Role of GPR161 in PKD (KIDNEY WEEK 2025) - "Studies on testing whether non-self-activatable variants of GPR161 can rescue the ciliary cAMP and cystogenesis in Inpp5e/Gpr161 dko IMCD3 cells are ongoing, as well as the animal studies. Conclusion Our current results suggest an intriguing possibility that GPR161 via self-activation constitutively produces the basal level of cAMP in primary cilia, which may elevate the ciliary cAMP to a level that triggers cystogenesis when PKD mutations cause abnormal increase of GPR161 or weaken certain counteracting mechanisms in cilia."

Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Integrating Network Analysis and Machine Learning Identifies Key Autism Spectrum Disorder Genes Linked to Immune Dysregulation and Therapeutic Targets. (PubMed, Genes (Basel)) - "This study effectively bridges the basic transcriptomic discoveries and clinical applications in ASD research. The findings contribute to a better understanding of the etiology of ASD and provide potential therapeutic leads. Future research could focus on validating these potential drugs in clinical studies, as well as further exploring the biological functions of the identified genes to develop more targeted and effective treatments for ASD."

Journal • Autism Spectrum Disorder • Genetic Disorders • GABRE • NLRP3 • TFAP2A

Transcriptional Consequences of MeCP2 Knockdown and Overexpression in Mouse Primary Cortical Neurons. (PubMed, Int J Mol Sci) - "Among these, RTT-associated candidates such as Plcb1, Gpr161, Mknk2, Rgcc, and Abhd6 were linked to disrupted synaptic signaling and neurogenesis, while ASD-associated genes, including Aim2, Mcm6, Pcdhb9, and Cbs, implicated neuroinflammation and metabolic stress. These findings establish a compact and mechanistically informative set of MeCP2-responsive genes, which enhance our understanding of transcriptional dysregulation in RTT and ASD and nominate molecular markers for future functional validation and therapeutic exploration."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Genetic Disorders • Inflammation • Movement Disorders • Psychiatry • MCM6 • MKNK2

Exploring the Potential of FLASH Proton Therapy in Medulloblastoma: Insights from Cerebellar and Tumor Organoids (ASTRO 2025) - "For medulloblastoma organoids, GPR161 knockout iPS cells were generated via gene editing to replicate the induction of SHH-type medulloblastoma... This study elucidated the differential cellular responses of cerebellar and medulloblastoma organoids to UHDR proton irradiation. The results suggest that FLASH proton therapy may contribute to reducing toxicity in normal cerebellar tissue while maintaining its efficacy against medulloblastoma."

Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • CASP3 • FGF2 • MYCN • PAX6

Identification of novel interacting proteins of FUZ and GPR161. (PubMed, bioRxiv) - "Among the identified proteins, we prioritized FKBP8 and confirmed its biochemical interactions with both FUZ and GPR161 exclusively. In summary, our proteomic profiling uncovered the protein network of FUZ and GPR161, revealing their individual and cooperative functions in multiple cellular processes."

Journal

Compound heterozygous ROBO1 gene variants in a neonate with congenital hypopituitarism, dysmorphic features and midline abnormalities: a case report and review of the literature. (PubMed, J Pediatr Endocrinol Metab) - "This case, together with accumulating evidence, supports ROBO1 as a potential causative gene for CH. ROBO1 should be considered during genetic evaluation of patients with CH and midline abnormalities. The co-occurrence of NOTCH3 and GPR161 variants raises the possibility of an oligogenic or multigenic etiology. The cross-talk between ROBO/SLIT and NOTCH signaling pathways may contribute to the complex phenotype observed and warrants further functional investigation."

Journal • Endocrine Disorders • Growth Hormone Deficiency • NOTCH3 • ROBO1

GPR161 mechanosensitivity at the primary cilium drives neuronal saltatory migration. (PubMed, Sci Adv) - "We demonstrate that GPR161 activates a recently discovered cAMP/PKA signaling pathway leading to the phosphorylation of NDE1, a dynein complex regulator, and microtubule organization to regulate migration. These findings unveil a critical role of mechanosensation in neuronal migration, regulating the rhythmicity of migration, in concert with the externalization/internalization dynamics of the primary cilium."

Journal

Skeletal ciliopathy variants of dynein-2 DYNC2LI1 subunit impair osteogenic differentiation of mesenchymal stem cells. (PubMed, J Cell Sci) - "Dync2li1-knockout cells expressing disease-causing DYNC2LI1 variants demonstrated defects in the retrograde ciliary protein trafficking, including Hedgehog pathway GPCRs, Smoothened and GPR161...By contrast, osteogenic differentiation via BMP signaling was derepressed in Dync2li1-knockout cells. This suggests that skeletal ciliopathies caused by DYNC2LI1 variants could be attributable in part to impaired osteogenic differentiation due to defects in Hedgehog signaling, resulting from defects in retrograde ciliary protein trafficking."

Journal • GLI3

β-Arrestin mediates the export of ciliary GPR161 but not Smoothened together with the BBSome and IFT machinery. (PubMed, J Cell Sci) - "We here propose that phosphorylated GPR161 recruits β-arrestins, converting them into their activated conformation. Activated β-arrestins then interact with the BBSome, which connects them to the IFT machinery to facilitate GPR161 export."

Journal • Bardet–Biedl Syndrome • Inherited Retinal Dystrophy • Ophthalmology • ARRB1

Differences in neuronal ciliation rate and ciliary content revealed by systematic imaging-based analysis of hiPSC-derived models across protocols. (PubMed, Front Cell Dev Biol) - "Interestingly, we found that while GPR161 signal almost completely disappeared from cilia upon Sonic hedgehog (SHH) stimulation in NSCs and immature neurons, this was not the case in more mature neurons, suggesting a possible developmental time window for cilia-dependent SHH signaling. Taken together, our results provide a systematic description of cilia in hiPSC-derived neuronal cells generated with different protocols, underscoring the importance of selecting the optimal model system and controls for investigating primary cilia in hiPSC-derived neuronal cells."

Journal • ARL13B

Dissection of Gαs and Hedgehog signaling crosstalk reveals therapeutic opportunities to target adenosine receptor 2b in Hedgehog-dependent tumors. (PubMed, bioRxiv) - "Tumors from Gαs pathway inactivation are independent of the canonical Hedgehog regulators SMO and GPR161, establishing them as an SMO-independent oncogenic Hedgehog signaling model. Finally, we demonstrate that activation of the Gαs-coupled adenosine 2B receptor counteracts oncogenic SMO, reducing Hedgehog signaling and tumor formation and offering a potential therapeutic strategy for BCC."

Journal • Basal Cell Carcinoma • Non-melanoma Skin Cancer • Oncology

Genomic landscape of medulloblastoma subtypes in an Asian cohort. (PubMed, Transl Cancer Res) - "All germline variants of the ten susceptibility genes of interest (APC, BRCA2, PTCH1, PTCH2, ELP1, SUFU, CTNNB1, SMARCA4, GPR161, and TP53) were annotated and validated...This study provides valuable insights into the genetic landscape of MB in an Asian cohort, emphasizing the importance of population-specific research. The subtype-specific germline variant landscape identified in this study contributes to the understanding of MB and its genetic underpinnings in Asian populations, potentially guiding future research and therapeutic strategies."

Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • APC • BRCA2 • CTNNB1 • PTCH1 • PTCH2 • SMARCA4 • TP53

BBSome-deficient cells activate intraciliary CDC42 to trigger actin-dependent ciliary ectocytosis. (PubMed, EMBO Rep) - "Inhibition of CDC42 in BBSome-deficient cells decreases the frequency and duration of ciliary actin polymerization events, causing buildup of G protein coupled receptor 161 (GPR161) in bulges along the axoneme during Sonic Hedgehog signaling. Overall, our study identifies CDC42 as a key trigger of ciliary ectocytosis. Hyperactive ciliary CDC42 and ectocytosis and the resulting loss of ciliary material might contribute to BBS disease severity."

Journal • Bardet–Biedl Syndrome • Inherited Retinal Dystrophy • Ophthalmology • CDC42

Obesity Associated Proteins Dynamically Localize to Cilia in the Mouse Brain (OBESITY WEEK 2024) - "For example, some GPCRs (SSTR3 and GPR161) appear to be removed from cilia in a ligand dependent manner in cells... Certain ciliary proteins appear to dynamically localize under different physiological conditions in vivo, while others appear to remain relatively static in their cilia localization. Alternatively, a subset of cilia may be dynamic and are not revealed in our analysis. A better understanding of the subcellular localization dynamics of ciliary signaling proteins could reveal new mechanisms regulating behavior and energy homeostasis."

Preclinical • Genetic Disorders • Obesity • ARL13B

Determining the Pathogenic Mechanism Underlying Childhood ADPKD Caused by a Monoallelic Pathogenic Variant in NEK8 (KIDNEY WEEK 2024) - "Although the ciliary level of GPR161 remained unchanged, SAG induced less accumulation of Smoothened and Gli3 in NEK8R45W cilia than WT, indicating a weaker activation of the Hedgehog (Hh) signaling... We further study the characteristics of the monoallelic NEK8 p.Arg45Trp and determined that the kinase activity of NEK8 in cilia is necessary for the ciliary trafficking of the PC complex, activation of Hh signaling, and epithelial morphogenesis. These signaling pathways may collectively contribute to the establishment and maintenance of renal tubule structures. Understanding the crosstalk between these pathways via studying the role of NEK8R45W may reveal potential drug targets for the treatment of ADPKD in children."

Clinical • Autosomal Dominant Polycystic Kidney Disease • Nephrology • Polycystic Kidney Disease • Renal Disease • GLI3 • PKD1 • PRKD1

Linkage between Fuz and Gpr161 genes regulates sonic hedgehog signaling during mouse neural tube development. (PubMed, Development) - "The Fuz protein biochemically interacts with Gpr161, and Fuz regulates Gpr161-mediated ciliary localization, a process that might utilize β-arrestin 2. Our study characterizes a previously unappreciated Gpr161-Fuz axis that regulates Shh signaling during mouse neural tube development."

Journal • Preclinical • ARRB1

Frequency of pathogenic germline variants in pediatric medulloblastoma survivors. (PubMed, Front Oncol) - "Most cases are sporadic, but well characterized germline alterations in APC, ELP1, GPR161, PTCH1, SUFU, and TP53 predispose to medulloblastoma...Approximately one in eight pediatric medulloblastoma survivors had an autosomal dominant P/LP CSG variant. We confirm several known associated genes and identify novel genes that may be important in medulloblastoma."

Journal • Brain Cancer • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • APC • PTCH1 • TP53

In vivo and in vitro anti-inflammation of Rhapontici Radix extract on mastitis via TMEM59 and GPR161. (PubMed, J Ethnopharmacol) - "ICAB is a prominent antioxidant in RRE. RRE and ICAB reduce mammary inflammation via MAPK and NF-κB pathways and the interaction between TMEM59 and GPR161 mediates the control of ICAB in NF-κB signaling."

Journal • Preclinical • Inflammation • IL1B • IL6 • MAPK8 • TNFA

The evolutionary impact of childhood cancer on the human gene pool. (PubMed, Nat Commun) - "For six genes [ELP1, GPR161, VHL and SDHA/B/C], a clear lack of mutational constraint calls the pediatric penetrance and/or severity of associated cancers into question. Conversely, out of 23 known pCPS genes associated with biallelic risk, two [9%, DIS3L2 and MSH2] show significant constraint, indicating that they may monoallelically increase childhood cancer risk. In summary, we show that population genetic data provide empirical evidence that heritable childhood cancer leads to natural selection powerful enough to have significantly impacted the present-day gene pool."

Journal • Oncology • Pediatrics • MSH2 • SDHA

GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway. (PubMed, Nat Struct Mol Biol) - "By contrast, a protein kinase A-binding site in the GPR161 C terminus is critical in suppressing GLI2 ciliary accumulation. Our work highlights how structural features of GPR161 interface with the Hedgehog pathway and sets a foundation to understand the role of GPR161 function in other signaling pathways."

Journal • GLI2

Pax3 lineage-specific deletion of Gpr161 is associated with spinal neural tube and craniofacial malformations during embryonic development. (PubMed, Dis Model Mech) - "In particular, the closed form of spina bifida is partly due to the reduced Pax3 and Cdx4 gene expression of the posterior dorsal neural tubes of Gpr161 mutant embryos involving decreased Wnt signaling, whereas Shh signaling was increased. We describe a novel role for Gpr161 in the development of posterior neural tubes and confirm its role in CNC- and somite-derived skeletogenesis and midbrain morphogenesis in mice."

Journal • PAX3

Context-dependent ciliary regulation of hedgehog pathway repression in tissue morphogenesis. (PubMed, PLoS Genet) - "We studied hedgehog pathway repression by the GPCR GPR161, and the ankyrin repeat protein ANKMY2 that direct cAMP/protein kinase-A signaling by cilia in GLI-R generation...Our results show complex tissue-specific GLI-effector requirements in morphogenesis and point to tissue-specific GLI-R thresholds generated by cilia in hedgehog pathway repression. Broadly, our study sets up a conceptual framework for rationalization of different modes of signaling generated by the primary cilium in mediating morphogenesis in diverse tissues."

Journal • GLI2 • GLI3

Determine the Pathogenic Mechanism Underlying Infantile ADPKD Caused by a Novel Monoallelic NEK8 Mutation (KIDNEY WEEK 2023) - "The level of GPR161 in cilia remained the same with or without Nek8... We found that a novel ADPKD variant of NEK8 (R45W) selectively repressed the ciliary level of PC2. In future, we will seek NEK8 partners in cilia that are specifically affected by this single-point mutation in NEK8. Our work will provide critical information to the understanding of PC trafficking in cilia and ADPKD etiology."

Autosomal Dominant Polycystic Kidney Disease • Polycystic Kidney Disease • PKD1 • PKD2 • PRKD1

Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive G signaling. (PubMed, Nat Commun) - "The structures of GPR161 and GPR61 reveal that the second extracellular loop (ECL2) penetrates into the orthosteric pocket, possibly contributing to constitutive activity. Our work definitively confirms lysoPS as an endogenous GPR174 ligand and suggests that high constitutive activity of some orphan GPCRs could be accounted for by their having naturally abundant ligands."

Journal

Rgl-exomiR-7972, a novel plant exosomal microRNA derived from fresh Rehmanniae Radix, ameliorated lipopolysaccharide-induced acute lung injury and gut dysbiosis. (PubMed, Biomed Pharmacother) - "Therefore, miR-7972 derived from fresh R. Radix alleviated LPS-induced lung inflammation by targeting the GPR161-mediated Hedgehog pathway, recovering gut microbiota dysbiosis. It also provided a new direction for gaining novel bioactivity nucleic acid drugs and broadening the knowledge on cross-kingdom physiological regulation through miRNAs."

Journal • Acute Lung Injury • Inflammation • Metabolic Disorders • Pneumonia • Respiratory Diseases • IL1B • IL6 • TNFA