<scp><i>GNAO1</i></scp> Haploinsufficiency: The Milder End of the <scp><i>GNAO1</i></scp> Phenotypic Spectrum

Galosi, Serena; Novelli, Maria; Di Rocco, Martina; Flex, Elisabetta; Messina, Elena; Pollini, Luca; Parrini, Elena; Pisani, Francesco; Guerrini, Renzo; Leuzzi, Vincenzo; Martinelli, Simone

doi:10.1002/mds.29585

Cited by 8 publications

(3 citation statements)

References 7 publications

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“…Further evidence is essential to determine whether more severe phenotypes of GNAO1 -RD correlate with a higher incidence of dyskinetic crises. Notably, some patients with milder phenotypes, characterized by a more dystonic presentation, occasionally limited to isolated cervical dystonia, have never experienced dyskinetic crises ( 20 , 37 ). It is crucial to highlight that individuals with GNAO1 -RD might encounter dyskinetic crises several years after the onset of dystonia.…”

Section: Resultsmentioning

confidence: 99%

Dyskinetic crisis in GNAO1-related disorders: clinical perspectives and management strategies

Domínguez Carral,

Reinhard,

Ebrahimi-Fakhari

et al. 2024

Front. Neurol.

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BackgroundGNAO1-related disorders (GNAO1-RD) encompass a diverse spectrum of neurodevelopmental and movement disorders arising from variants in the GNAO1 gene. Dyskinetic crises, marked by sudden and intense exacerbations of abnormal involuntary movements, present a significant challenge in GNAO1-RD.ObjectivesThis study aimed to establish a standardized framework for understanding dyskinetic crises, addressing crucial aspects such as definition, triggers, diagnostic criteria, complications, and management strategies.MethodsA Delphi consensus process was conducted involving international experts in GNAO1-RD. The panel of thirteen experts participated in three voting rounds, discussing 90 statements generated through a literature review and clinical expertise.ResultsConsensus was achieved on 31 statements, defining dyskinetic crises as abrupt, paroxysmal episodes involving distinct abnormal movements in multiple body regions, triggered by emotional stress or infections. Dyskinetic crises may lead to functional impairment and complications, emphasizing the need for prompt recognition. While individualized pharmacological recommendations were not provided, benzodiazepines and clonidine were suggested for acute crisis management. Chronic treatment options included tetrabenazine, benzodiazepines, gabapentin, and clonidine. Deep brain stimulation should be considered early in the treatment of refractory or prolonged dyskinetic crisis.ConclusionThis consensus provides a foundation for understanding and managing dyskinetic crises in GNAO1-RD for clinicians, caregivers, and researchers. The study emphasizes the importance of targeted parental and caregiver education, which enables early recognition and intervention, thereby potentially minimizing both short- and long-term complications. Future research should concentrate on differentiating dyskinetic crises from other neurological events and investigating potential risk factors that influence their occurrence and nature. The proposed standardized framework improves clinical management, stakeholder communication, and future GNAO1-RD research.

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Section: Resultsmentioning

confidence: 99%

Dyskinetic crisis in GNAO1-related disorders: clinical perspectives and management strategies

Domínguez Carral,

Reinhard,

Ebrahimi-Fakhari

et al. 2024

Front. Neurol.

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“…Given the effect of the pathogenic Gαo variants over the binding and chaperone function of Ric8 for several Gα subunits, the neomorphic Gαo-Ric8 interaction may lie at the core of the disease dominance, affecting not only Gαo signaling, but also imbalancing the entire neuronal GPCR signaling network. This neomorphic property might explain why several Gαo variants, despite been poorly expressed, lead to the severe DEE17 phenotype instead of the milder dystonic phenotype recently linked to GNAO1 haploinsufficiency ( 19 , 44 , 45 ).…”

Section: Discussionmentioning

confidence: 99%

Neomorphic Gαo mutations gain interaction with Ric8 proteins in GNAO1 encephalopathies

Solis,

Koval,

Valnohova

et al. 2024

Journal of Clinical Investigation

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GNAO1 mutated in pediatric encephalopathies encodes the major neuronal G protein Gαo. Of the more than 80 pathogenic mutations, most are single amino acid substitutions spreading across the Gαo sequence. We performed extensive characterization of Gαo mutants, showing abnormal GTP uptake and hydrolysis and deficiencies in binding Gβγ and RGS19. Plasma membrane localization of Gαo was decreased for a subset of mutations that leads to epilepsy; dominant interactions with GPCRs also emerged for the more severe mutants. Pathogenic mutants massively gained interaction with Ric8A and, surprisingly, Ric8B proteins, relocalizing them from cytoplasm to Golgi. Of these 2 mandatory Gα-subunit chaperones, Ric8A is normally responsible for the Gαi/Gαo, Gαq, and Gα12/Gα13 subfamilies, and Ric8B solely responsible for Gαs/Gαolf. Ric8 mediates the disease dominance when engaging in neomorphic interactions with pathogenic Gαo through imbalance of the neuronal G protein signaling networks. As the strength of Gαo-Ric8B interactions correlates with disease severity, our study further identifies an efficient biomarker and predictor for clinical manifestations in GNAO1 encephalopathies. Our work uncovers the neomorphic molecular mechanism of mutations underlying pediatric encephalopathies and offers insights into other maladies caused by G protein malfunctioning and further genetic diseases.

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“…Codons 203, 209, and 246 represent pathogenic variant hotspots, occurring in about 50% of cases. A different class of variants leading to GNAO1 haploinsufficiency has recently been associated with a relatively mild and delayed-onset dystonia phenotype (3;4;5). Recently, the examination of several patients with distinct GNAO1 variants resulted in a new clinical severity score (6).…”

Section: Introductionmentioning

confidence: 99%

Cortical neurons obtained from patient-derived iPSCs with GNAO1 p.G203R variant show altered differentiation and functional properties

Benedetti,

D’Andrea,

Colantoni

et al. 2023

Preprint

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Pathogenic variants in the GNAO1 gene, encoding for the α subunit of a heterotrimeric guanine nucleotide-binding protein (Go), have been linked to encephalopathy characterized by different combinations of neurological symptoms, including developmental delay, hypotonia, epilepsy and hyperkinetic movement disorder with life-threatening paroxysmal exacerbations. Currently there are no curative but only symptomatic treatments, and little is known on the pathophysiology of the disease. In this paper we report the characterization of a new in vitro model system based on patient-derived induced pluripotent stem cells (iPSCs) carrying the recurrent p.G203R amino acid substitution in Gαo, and a genetically corrected isogenic control line. Upon induction of differentiation into cortical neurons, patient's cells showed altered expression of neural genes as well as premature and defective differentiation processes. Functional characterization showed lower basal intracellular free calcium concentration ([Ca2+]i), reduced frequency of spontaneous activity, and a smaller response to several neurotransmitters. These results suggest that the GNAO1 pathogenic variant causes a neurodevelopmental phenotype characterized by aberrant differentiation of neural precursor cells leading to a significant alteration of neuronal communication and signal transduction.

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GNAO1 Haploinsufficiency: The Milder End of the GNAO1 Phenotypic Spectrum

Cited by 8 publications

References 7 publications

Dyskinetic crisis in GNAO1-related disorders: clinical perspectives and management strategies

Dyskinetic crisis in GNAO1-related disorders: clinical perspectives and management strategies

Neomorphic Gαo mutations gain interaction with Ric8 proteins in GNAO1 encephalopathies

Cortical neurons obtained from patient-derived iPSCs with GNAO1 p.G203R variant show altered differentiation and functional properties

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