Identification of a Mosaic Activating Mutation in GNA11 in Atypical Sturge-Weber Syndrome.
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ABSTRACT:
SUBMITTER: Thorpe J
PROVIDER: S-EPMC8483769 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
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Identification of a Mosaic Activating Mutation in GNA11 in Atypical Sturge-Weber Syndrome.
Thorpe Jeremy J Frelin Laurence P LP McCann Meghan M Pardo Carlos A CA Cohen Bernard A BA Comi Anne M AM Pevsner Jonathan J
The Journal of investigative dermatology 20200807 3
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Project description: Not available
| S-EPMC3997529 | biostudies-literature
Project description:BackgroundSturge-Weber syndrome is a rare neurovascular disorder associated with capillary malformation, seizures, cognitive impairments, and stroke-like episodes (SLEs), arising from a somatic activating mutation in GNAQ. Studies suggest this mutation may cause hyperactivation of the mammalian target of rapamycin pathway. Sirolimus is an mammalian target of rapamycin inhibitor studied in other vascular anomalies and a potentially promising therapy in Sturge-Weber syndrome.MethodsTen patients with Sturge-Weber syndrome brain involvement and cognitive impairments were enrolled. Oral sirolimus was taken for six months (maximum dose: 2 mg/day, target trough level: 4-6 ng/mL). Neuropsychological testing, electroencephalography, and port-wine score were performed at baseline and after six months on sirolimus. Neuroquality of life, adverse events, and Sturge-Weber Syndrome Neurological Score (neuroscore) were recorded at each visit.ResultsSirolimus was generally well tolerated; one subject withdrew early. Adverse events considered related to sirolimus were mostly (15/16) grade 1. A significant increase in processing speed was seen in the overall group (P = 0.031); five of nine patients with available data demonstrated statistically rare improvement in processing speed. Improvements were seen in the neuroquality of life subscales measuring anger (P = 0.011), cognitive function (P = 0.015), and depression (P = 0.046). Three subjects experiencing SLEs before and during the study reported shortened recovery times while on sirolimus.ConclusionsSirolimus was well tolerated in individuals with Sturge-Weber syndrome and may be beneficial for cognitive impairments, especially in patients with impaired processing speed or a history of SLE. A future, randomized, placebo-controlled trial of sirolimus in patients with Sturge-Weber syndrome is needed to further understand these potentially beneficial effects.
| S-EPMC8209677 | biostudies-literature
Project description:Sturge-Weber syndrome is a vascular malformation syndrome consisting of a facial port-wine birthmark associated with malformed leptomeningeal blood vessels and a choroid "angioma" of the eye. It is a rare neurocutaneous disorder that occurs sporadically, is not inherited, and is caused by a somatic mosaic mutation in GNAQ. In patients with Sturge-Weber syndrome, brain involvement typically presents in infancy with seizures, strokes, and stroke-like episodes, and a range of neurologic impairments. Standard treatment includes laser therapy for the birthmark, control of glaucoma through eyedrops or surgery, and the use of anticonvulsants. Increasingly low-dose aspirin is offered. Treatment with propranolol has been tried generally without the dramatic results seen in hemangiomas. Treatment with an anticonvulsant or low-dose aspirin or both before the onset of seizures is an option. Surgical resection may be offered to those whose seizures are medically refractory. Endocrine, medical rehabilitation and cognitive comorbidities are important to manage. In the future, new therapeutic options are likely to be offered stemming from preclinical studies and small pilot clinical trials currently ongoing. Discovery of the causative somatic mosaic mutation suggests new insights into the pathophysiology of this vascular malformation disorder, and potential novel treatment strategies for future study. The mutation results in constitutive overactivation of the Ras-Raf-MEK-ERK and the HIPPO-YAP pathways and inhibitors of these pathways may in the future prove useful in the treatment of Sturge-Weber syndrome.
| S-EPMC4943027 | biostudies-literature
Project description:Sturge-Weber syndrome is a rare nonhereditary developmental condition with neurological and skin disorder, characterized by presence of port wine stain on the face along with ocular disorders, oral manifestations and leptomeningeal angiomas. Here we present an unusual case of Sturge-Weber syndrome with osseous hypertrophy of maxilla.
| S-EPMC3681312 | biostudies-literature
Project description:BackgroundThe Sturge-Weber syndrome is a sporadic congenital neurocutaneous disorder characterized by a port-wine stain affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary venous vessels in the leptomeninges of the brain and choroid, glaucoma, seizures, stroke, and intellectual disability. It has been hypothesized that somatic mosaic mutations disrupting vascular development cause both the Sturge-Weber syndrome and port-wine stains, and the severity and extent of presentation are determined by the developmental time point at which the mutations occurred. To date, no such mutation has been identified.MethodsWe performed whole-genome sequencing of DNA from paired samples of visibly affected and normal tissue from 3 persons with the Sturge-Weber syndrome. We tested for the presence of a somatic mosaic mutation in 97 samples from 50 persons with the Sturge-Weber syndrome, a port-wine stain, or neither (controls), using amplicon sequencing and SNaPshot assays, and investigated the effects of the mutation on downstream signaling, using phosphorylation-specific antibodies for relevant effectors and a luciferase reporter assay.ResultsWe identified a nonsynonymous single-nucleotide variant (c.548G→A, p.Arg183Gln) in GNAQ in samples of affected tissue from 88% of the participants (23 of 26) with the Sturge-Weber syndrome and from 92% of the participants (12 of 13) with apparently nonsyndromic port-wine stains, but not in any of the samples of affected tissue from 4 participants with an unrelated cerebrovascular malformation or in any of the samples from the 6 controls. The prevalence of the mutant allele in affected tissues ranged from 1.0 to 18.1%. Extracellular signal-regulated kinase activity was modestly increased during transgenic expression of mutant Gαq.ConclusionsThe Sturge-Weber syndrome and port-wine stains are caused by a somatic activating mutation in GNAQ. This finding confirms a long-standing hypothesis. (Funded by the National Institutes of Health and Hunter's Dream for a Cure Foundation.).
| S-EPMC3749068 | biostudies-literature
Project description:PurposeSturge-Weber syndrome (SWS) and sympathetic ophthalmia (SO) are unusual pathologies. Their association has not been previously reported. This unusual diagnosis can be elucidated by clinical suspicion.MethodsCase report of a 22-month-old female with SO.ResultsSWS with a unilateral diffuse choroidal hemangioma. The exciting eye had multiple surgeries for glaucoma that required enucleation. Clinical picture of SO was found on the sympathizing eye. Atypical histopathology (nongranulomatous choroidal infiltrate and perivascular mononuclear cells) is found in the enucleated eye.ConclusionsTo the best of the authors' knowledge, this is the first description of an association of SWS, diffuse choroidal hemangioma, infantile glaucoma, and SO. Many confounding factors are present (ie, multiple surgeries, risk of infectious endophthalmitis). Therefore, a high index of suspicion must be kept in mind to make the diagnosis. We aim to raise awareness of such a devastating condition in a pediatric patient with many comorbidities.
| S-EPMC8291720 | biostudies-literature
Project description:AimWe assessed the utilization of the National Institutes of Health Quality of Life in Neurological Disorders (Neuro-QoL) in pediatric patients with Sturge-Weber syndrome, a rare neurovascular disorder which frequently results in seizures, brain atrophy, calcification, and a range of neurological impairments.MethodsSubjects were seen clinically and consented for research. All 22 patients filled out the Pediatric Neuro-QoL. The Neuro-QoL subscores were converted to T-scores to compare with the referenced control population. Twenty-one participants also filled out the Brain Vascular Malformation Consortium Database Questionnaire containing data pertaining to Sturge-Weber syndrome-related medical history, medications, comorbidities, and family history. All data were analyzed with a significance threshold of P < 0.05.ResultsCognitive function quality of life was significantly lower (P < 0.001) in pediatric patients with Sturge-Weber syndrome compared with referenced control subjects. Male gender (P = 0.02) was associated with lower cognitive function Neuro-QoL. The extent of skin (R = -0.46, P = 0.04), total eyelid port-wine birthmark (R = -0.56, P = 0.007), eye (R = -0.58, P = 0.005), and total Sturge-Weber syndrome involvement (R = -0.63, P = 0.002) were negatively correlated with cognitive function Neuro-QoL. A younger age at seizure onset was associated with lower cognitive function Neuro-QoL (hazard ratio = 0.90, P = 0.004) even after controlling for extent of brain, skin, or eye involvement. Antidepressant use was associated with lower cognitive function Neuro-QoL (P = 0.005), and cognitive function Neuro-QoL was negatively correlated with depression Neuro-QoL; however, after adjusting for depression this relationship was no longer significant.ConclusionsThe results suggest targeting cognitive function Neuro-QoL in treatment trials and reiterate the prognostic value of early seizure onset. In addition, sex-related differences were noted, which should be further studied.
| S-EPMC7288751 | biostudies-literature
Project description:BackgroundNinety percent of infants with Sturge-Weber syndrome (SWS) brain involvement have seizure onset before 2 years of age; this is associated with worse neurologic outcome. Presymptomatic treatment before seizure onset may delay seizure onset and improve outcome, as has been shown in other conditions with a high-risk of developing epilepsy such as tuberous sclerosis complex. Electroencephalogram (EEG) may be a biomarker to predict seizure onset. This retrospective clinical data analysis aims to assess impact of presymptomatic treatment in SWS.MethodsThis two-centered, IRB-approved, retrospective study analyzed records from patients with SWS brain involvement. Clinical data recorded included demographics, age of seizure onset (if present), brain involvement extent (unilateral versus bilateral), port-wine birthmark (PWB) extent, family history of seizure, presymptomatic treatment if received, neuroscore, and anti-seizure medication. EEG reports prior to seizure onset were analyzed.ResultsNinety-two patients were included (48 females), and 32 received presymptomatic treatment outside of a formal protocol (5 aspirin, 16 aspirin and levetiracetam; 9 aspirin and oxcarbazepine, 2 valproic acid). Presymptomatically-treated patients were more likely to be seizure-free at 2 years (15 of 32; 47% versus 7 of 60; 12%; p<.001). A greater percentage of presymptomatically-treated patients had bilateral brain involvement (38% treated versus 17% untreated; p=.026). Median hemiparesis neuroscore at 2 years was better in presymptomatically-treated patients. In EEG reports prior to seizure onset, the presence of slowing, epileptiform discharges, or EEG-identified seizures was associated with seizure onset by 2 (p=.001).ConclusionPresymptomatic treatment is a promising approach to children diagnosed with SWS prior to seizure onset. Further study is needed, including prospective drug trials, long-term neuropsychological outcome, and prospective EEG analysis to assess this approach and determine biomarkers for presymptomatic treatment.
| S-EPMC11090403 | biostudies-literature
Project description:Sturge-Weber syndrome (SWS) is a sporadic, congenital, neuro-cutaneous disorder characterized by a mosaic, capillary malformation. SWS and isolated capillary malformations are caused by a somatic activating mutation in GNAQ encoding the G protein subunit alpha-q protein. The missense mutation R183Q is the sole GNAQ mutation identified thus far in affected tissues of 90% of SWS patients. In this study, we sequenced skin biopsies of affected capillary malformations from 9 patients. We identified the R183Q mutation in nearly all samples, but one sample exhibited a Q209R mutation. This new mutation occurs at the same residue as the constitutively-activating Q209L mutation, commonly seen in tumors. However, Q209R is a rare variant in this gene. To compare the effect of the Q209R mutation on downstream signaling, we performed reporter assays with a GNAQ-responsive reporter co-transfected with either GNAQ WT, R183Q, Q209L, Q209R, or C9X (representing a null allele). Q209L showed the highest reporter activation, with R183Q and Q209R showing significantly lower activation. To determine whether these mutations had similar or different downstream consequences we performed RNAseq analysis in microvascular endothelial cells (HMEC-1) electroporated with the same GNAQ variants. The R183 and Q209 missense variants caused extensive dysregulation of a broad range of transcripts compared to the WT or null allele, confirming that these are all activating mutations. However, the missense variants exhibited very few differentially expressed genes (DEGs) when compared to each other. These data suggest that these activating GNAQ mutations differ in magnitude of activation but have similar downstream effects.
2022-07-28 | GSE199978 | GEO
Project description:Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations affecting skin, eyes and leptomeninges of the brain, which can lead to glaucoma, seizures and intellectual disability. The discovery of a disease-causing somatic missense mutation in the GNAQ gene, encoding an alpha chain of heterotrimeric G-proteins, has initiated efforts to understand how G-proteins contribute to SWS pathogenesis. The mutation is predominantly detected in endothelial cells and is currently believed to affect downstream MAPK signalling. In this study of six Norwegian patients with classical SWS, we aimed to identify somatic mutations through deep sequencing of DNA from skin biopsies. Surprisingly, one patient was negative for the GNAQ mutation, but instead harbored a somatic mutation in GNB2 (NM_005273.3:c.232A>G, p.Lys78Glu), which encodes a beta chain of the same G-protein complex. The positions of the mutant amino acids in the G-protein are essential for complex reassembly. Therefore, failure of reassembly and continuous signalling is a likely consequence of both mutations. Ectopic expression of mutant proteins in endothelial cells revealed that expression of either mutant reduced cellular proliferation, yet regulated MAPK signalling differently, suggesting that dysregulated MAPK signalling cannot fully explain the SWS phenotype. Instead, both mutants reduced synthesis of Yes-associated protein (YAP), a transcriptional co-activator of the Hippo signalling pathway, suggesting a key role for this pathway in the vascular pathogenesis of SWS. The discovery of the GNB2 mutation sheds novel light on the pathogenesis of SWS and suggests that future research on targets of treatment should be directed towards the YAP, rather than the MAPK, signalling pathway.
| S-EPMC8522634 | biostudies-literature