RGS6: A Novel Gene Associated With Congenital Cataract, Mental Retardation, and Microcephaly in a Tunisian Family

Chograni, Manèl; Alkuraya, Fowzan S.; Mâazoul, Faouzi; Lariani, Imen; Chaabouni-Bouhamed, Habiba

doi:10.1167/iovs.14-15198

Cited by 9 publications

(6 citation statements)

References 19 publications

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“…The previously cited link between GNB5 and the R7-RGS RGS6 and RGS11 suggests that they are part of the same pathway. Consistent with this hypothesis, the members of a Tunisian family presenting with cataract, mental retardation and microcephaly were carriers of biallelic mutations in RGS6 86 . Another unpublished case harbouring mutation in RGS11 presented with overlapping neuropsychiatric phenotype (Sarah Montgomery, in litt ).…”

Section: Discussionmentioning

confidence: 60%

Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

et al. 2020

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BackgroundPathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia.MethodsWe used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse.ResultsWe delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5−/− mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/−, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5−/− mice. In contrast, Gnb5−/− mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients.ConclusionsOur data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5−/− mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening.

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Section: Discussionmentioning

confidence: 60%

Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

et al. 2020

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“…The possible significance of RGS6's role in schizophrenia is further supported by preliminary studies which also suggest that RGS7 and RGS9 may be differentially expressed in patients with schizophrenia (86,87) and may modulate brain responses to psychostimulants and antipsychotics (49,(88)(89)(90)(91)(92)(93). Finally, not only is there substantial evidence detailing the critical role of various R7 family members in proper vision (94-97) but a splice acceptor variant of RGS6 (c.1369-1G>C) has also been positively associated with the familial inheritance of congenital cataracts (26). Clearly, there is still significant work that needs to be done to elucidate the role of RGS6 in proper brain function.…”

Section: Alzheimer's Disease Schizophrenia and Eye-related Disordersmentioning

confidence: 84%

“…Finally, in terms of RGS6 function in negatively regulating heterotrimeric G protein signaling, the RGS domain is responsible for the GAP activity of RGS6, and other RGS proteins, and allows it to negatively regulate Gα i/o proteins (20). RGS6 specific modulation of Gα i/o protein activity has been implicated in the regulation of several disease states, particularly in the central nervous system (CNS), including the following: alcoholism (21), anxiety/depression (22), Parkinson's disease (23), and potentially Alzheimer's disease (24), schizophrenia (25), and vision (26). However, RGS6 is also unique in that it remains the only member of the R7 protein family that has been demonstrated to regulate G protein-independent pathways, as evidenced by its compelling pro-apoptotic and tumor suppressor actions in cancer (27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Ahlers

Chakravarti

Fisher

2016

AAPS J

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Abstract. Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gα i/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson's disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target.

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“…RGS6 expression was found to be negatively correlated with human pancreatic cancer (Ahlers et al, 2016), human breast cancer progression (Maity et al, 2011(Maity et al, , 2013Ahlers et al, 2016), and resistance to chemotherapies (Maity et al, 2013). Finally, in roles unrelated to cancer, a splice mutation in RGS6 was identified as a genetic cause of autosomal recessive congenital cataract, mental retardation, and microcephaly in two Tunisian siblings (Chograni et al, 2014).…”

Section: B the R7 Familymentioning

confidence: 94%

“…Within heart, RGS6 functions as an essential modulator of parasympathetic activation to prevent parasympathetic override and severe bradycardia (Yang et al, 2010). Studies relating RGS6 to human diseases are limited, although literature suggests that RGS6-specific modulation of Ga may be involved in regulating several central nervous system diseases such as alcoholism (Stewart et al, 2015), anxiety and depression (Stewart et al, 2014), Parkinson's disease (Bifsha et al, 2014), Alzheimer's disease (Moon et al, 2015), schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics, 2014), and vision (Chograni et al, 2014). Prolonged exposure to alcohol upregulates RGS6 protein in a brain region known as the ventral tegmental area of wild-type mice.…”

Section: B the R7 Familymentioning

confidence: 99%

Genetic Analysis of Rare Human Variants of Regulators of G Protein Signaling Proteins and Their Role in Human Physiology and Disease

et al. 2018

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Regulators of G protein signaling (RGS) proteins modulate the physiologic actions of many neurotransmitters, hormones, and other signaling molecules. Human RGS proteins comprise a family of 20 canonical proteins that bind directly to G protein-coupled receptors/G protein complexes to limit the lifetime of their signaling events, which regulate all aspects of cell and organ physiology. Genetic variations account for diverse human traits and individual predispositions to disease. RGS proteins contribute to many complex polygenic human traits and pathologies such as hypertension, atherosclerosis, schizophrenia, depression, addiction, cancers, and many others. Recent analysis indicates that most human diseases are due to extremely rare genetic variants. In this study, we summarize physiologic roles for RGS proteins and links to human diseases/traits and report rare variants found within each human RGS protein exome sequence derived from global population studies. Each RGS sequence is analyzed using recently described bioinformatics and proteomic tools for measures of missense tolerance ratio paired with combined annotation-dependent depletion scores, and protein post-translational modification (PTM) alignment cluster analysis. We highlight selected variants within the well-studied RGS domain that likely disrupt RGS protein functions and provide comprehensive variant and PTM data for each RGS protein for future study. We propose that rare variants in functionally sensitive regions of RGS proteins confer profound change-of-function phenotypes that may contribute, in newly appreciated ways, to complex human diseases and/or traits. This information provides investigators with a valuable database to explore variation in RGS protein function, and for targeting RGS proteins as future therapeutic targets.

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RGS6: A Novel Gene Associated With Congenital Cataract, Mental Retardation, and Microcephaly in a Tunisian Family

Cited by 9 publications

References 19 publications

Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Genetic Analysis of Rare Human Variants of Regulators of G Protein Signaling Proteins and Their Role in Human Physiology and Disease

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