Mutations in<i>GNAL</i>

Kumar, Kishore R.; Lohmann, Katja; Masuho, Ikuo; Miyamoto, Ryosuke; Ferbert, A.; Lohnau, Thora; Kasten, Meike; Hagenah, Johann; Brüggemann, Norbert; Graf, Julia; Münchau, Alexander; Kostić, Vladimir; Sue, Carolyn M.; Domingo, Aloysius; Rosales, Raymond L.; Lee, Lilian V.; Freimann, Karen; Westenberger, Ana; Mukai, Yukinori; Kawarai, Toshitaka; Kaji, Ryuji; Klein, Christine; Martemyanov, Kirill A.; Schmidt, Alexander

doi:10.1001/jamaneurol.2013.4677

Cited by 72 publications

(21 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In type I ACS, a single mutant allele is sufficient to cause the disease because of the dominant-negative action of Gα i3 variants, whereas in other diseases a single G protein mutant allele causes haploinsufficiency. For example, primary torsion dystonia, craniocervical dystonia or Albright’s Hereditary Osteodystrophy (AHO) can be caused by non-sense or missense mutations that lead to no protein or severe protein structural defects (5, 9, 10). Nougaret night blindness is caused by a missense mutation in Gαt, but it has been unequivocally established that the disease arises from a loss of function not accompanied by any dominant-negative function (7, 8).…”

Section: Discussionmentioning

confidence: 99%

“…The majority of G protein-associated mutations have been identified in genes encoding Gα subunits (5, 6) and are broadly classified as loss-of-function or gain-of-function mutations. Loss-of-function mutations in various Gα proteins are associated with the congenital diseases Albright’s Hereditary Osteodystrophy (Gα s ), Nougaret night blindness (Gα t ) and two types of dystonia (Gα olf ) (5, 7–10). On the other hand, gain-of-function mutations are somatic and exert a dominant effect by rendering the Gα subunit constitutively active.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dominant-negative Gα subunits are a mechanism of dysregulated heterotrimeric G protein signaling in human disease

et al. 2016

View full text Add to dashboard Cite

Auriculo-Condylar Syndrome (ACS), a rare condition that impairs craniofacial development, is caused by mutations in a G protein-coupled receptor (GPCR) signaling pathway. In mice, disruption of signaling by the endothelin type A receptor (ETAR), which is mediated by the G protein subunit Gαq/11 and subsequently phospholipase C (PLC), impairs neural crest cell differentiation that is required for normal craniofacial development. Some ACS patients have mutations in GNAI3, which encodes Gαi3, but it is unknown whether this G protein has a role within the ETAR pathway. Here, we used a Xenopus model of vertebrate development, in vitro biochemistry, and biosensors of G protein activity in mammalian cells to systematically characterize the phenotype and function of all known ACS-associated Gαi3 mutants. We found that ACS-associated mutations in GNAI3 produce dominant-negative Gαi3 mutant proteins that couple to ETAR but cannot bind and hydrolyze guanosine triphosphate, resulting in the prevention of endothelin-mediated activation of Gαq/11 and PLC. Thus, ACS is caused by functionally dominant-negative mutations in a heterotrimeric G protein subunit.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dominant-negative Gα subunits are a mechanism of dysregulated heterotrimeric G protein signaling in human disease

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The degraded action selection which underpins these involuntary movements have long been thought to be the consequence of dysfunction within the basal ganglia, based on clinical observation (Berardelli et al, 1998;Bhatia & Marsden, 1994), neuroimaging (Colosimo et al, 2005;Draganski et al, 2009;Naumann et al, 1998;Zoons, Booij, Nederveen, Dijk, & Tijssen, 2011), and its secondary association with "extra-pyramidal" disorders (Burke et al, 1982;Louis, Lee, Quinn, & Marder, 1999;Rivest, Quinn, & Marsden, 1990). The recent identification of families with novel mutations in genes which encode proteins richly expressed within the striatum implicated in dopaminergic signal transduction, e.g., GNAL (Kumar et al, 2014), and ANO3 (Charlesworth et al, 2012) has reignited interest in "old ideas" about dopaminergic dysfunction being a common pathophysiological hallmark (Goodchild, Grundmann, & Pisani, 2013). For patients with cervical dystonia, detailed molecular and neurophysiological understanding of the nature of this derangement in signaling is crucial for the development of new treatments.…”

Section: Introductionmentioning

confidence: 99%

Maladaptive striatal plasticity and abnormal reward-learning in cervical dystonia

Gilbertson

Humphries

Steele

2019

Preprint

View full text Add to dashboard Cite

In monogenetic generalized forms of dystonia, in vitro neurophysiological recordings have demonstrated direct evidence for abnormal plasticity at the level of the cortico‐striatal synapse. It is unclear whether similar abnormalities contribute to the pathophysiology of cervical dystonia, the most common type of focal dystonia. We investigated whether abnormal cortico‐striatal synaptic plasticity contributes to abnormal reward‐learning behavior in patients with focal dystonia. Forty patients and 40 controls performed a reward gain and loss avoidance reversal learning task. Participant's behavior was fitted to a computational model of the basal ganglia incorporating detailed cortico‐striatal synaptic learning rules. Model comparisons were performed to assess the ability of four hypothesized receptor specific abnormalities of cortico‐striatal long‐term potentiation (LTP) and long‐term depression (LTD): increased or decreased D1:LTP/LTD and increased or decreased D2: LTP/LTD to explain abnormal behavior in patients. Patients were selectively impaired in the post‐reversal phase of the reward task. Individual learning rates in the reward reversal task correlated with the severity of the patient's motor symptoms. A model of the striatum with decreased D2:LTP/ LTD best explained the patient's behavior, suggesting excessive D2 cortico‐striatal synaptic depotentiation could underpin biased reward‐learning in patients with cervical dystonia. Reversal learning impairment in cervical dystonia may be a behavioral correlate of D2‐specific abnormalities in cortico‐striatal synaptic plasticity. Reinforcement learning tasks with computational modeling could allow the identification of molecular targets for novel treatments based on their ability to restore normal reward‐learning behavior in these patients.

show abstract

“…A C-terminal fragment of the G protein receptor kinase 3 (GRK3ct) that binds to free Gβγ dimers fused to a luciferase serves as a BRET donor. Originally developed using Renilla luciferase as a BRET donor [4], the assay has been improved by substitution of the engineered NanoLuc from Oplophorus [2, 5]. This sensor is coexpressed with an unlabeled Gα subunit and a Gβγ dimer labeled with a BRET acceptor, generally the fluorescent protein venus (assembled by bimolecular fluorescence complementation; BiFC) [6].…”

Section: Introductionmentioning

confidence: 99%

Monitoring G Protein Activation in Cells with BRET

Masuho

Martemyanov

Lambert

2015

Methods in Molecular Biology

Self Cite

View full text Add to dashboard Cite

Summary Live-cell assays based on fluorescence and luminescence are now indispensable tools for the study of G protein signaling. Assays based on fluorescence and bioluminescence resonance energy transfer (FRET and BRET) have been particularly valuable for monitoring changes in second messengers, protein-protein interactions, and protein conformation. Here we describe a BRET assay that monitors the release of free Gβγ dimers after activation of heterotrimers containing Gα subunits from all four G protein subfamilies. This assay provides useful kinetic and pharmacological information with reasonably high throughput using standard laboratory equipment.

show abstract

Mutations inGNAL

Cited by 72 publications

References 14 publications

Dominant-negative Gα subunits are a mechanism of dysregulated heterotrimeric G protein signaling in human disease

Dominant-negative Gα subunits are a mechanism of dysregulated heterotrimeric G protein signaling in human disease

Maladaptive striatal plasticity and abnormal reward-learning in cervical dystonia

Monitoring G Protein Activation in Cells with BRET

Contact Info

Product

Resources

About