Computational analysis for GNAQ mutations: New insights on the molecular etiology of Sturge-Weber syndrome

Martins, Luciane; Giovani, Priscila Alves; Rebouças, Pedro Diniz; Brasil, Danieli Moura; Haiter-Neto, Francisco; Coletta, Ricardo D.; Machado, Renato Assis; Puppin-Rontani, Regina Maria; Nociti, Francisco Humberto; Kantovitz, Kamila Rosamilia

doi:10.1016/j.jmgm.2017.07.011

Cited by 33 publications

(24 citation statements)

References 42 publications

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“…a missense variant (c.548G>A, p.Arg183Gln) in the GNAQ gene within malformed tissue from SWS and nonsyndromic (isolated) port-wine stain, but neither in the patients' unaffected tissue nor healthy controls and unrelated vascular malformations. This particular variant was reported consistently by several other researchers [159][160][161][162], with high prevalence of approximately 90% in pathological samples from SWS and nonsyndromic port-wine stains alike (88% in 23 of 26 patients and 92% in 12 of 13 patients, respectively [159,160]).…”

Section: Arch Med Sci 11supporting

confidence: 80%

“…What is more, it has been observed that mutations in those two genes occur in tumors including melanomas [171][172][173]. Another activating mutation of GNAQ (c.626A>T; p.Gln-209Leu) has been reported in SWS, phakomatosis pigmentovascularis (a similarly sporadic condition combining port-wine stain and pigmentary lesion) but also in uncomplicated, congenital hemangiomas and in several melanocytic neoplasms and malignant intraocular tumors including uveal melanomas [160,174,175].…”

Section: Arch Med Sci 11mentioning

confidence: 99%

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Genetic syndromes with vascular malformations – update on molecular background and diagnostics

et al. 2021

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Vascular malformations are present in a great variety of congenital syndromes, either as the predominant or additional feature. They pose a major challenge to the clinician: due to significant phenotype overlap, a precise diagnosis is often difficult to obtain, some of the malformations carry a risk of life threatening complications and, for many entities, treatment is not well established. To facilitate their recognition and aid in differentiation, we present a selection of notable congenital disorders of vascular system development, distinguishing between the heritable germinal and sporadic somatic mutations as their causes. Clinical features, genetic background and comprehensible description of molecular mechanisms is provided for each entity.

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Section: Arch Med Sci 11supporting

confidence: 80%

Section: Arch Med Sci 11mentioning

confidence: 99%

Genetic syndromes with vascular malformations – update on molecular background and diagnostics

et al. 2021

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“…Biochemical data shows that GNAQ (R183Q) mutation is located GTP binding domain and induces very minimal ERK activation [77,78,79]. In a silico protein-interaction model, it is proposed that the R183G mutation lost two hydrogen bonds between the Gαq and GDP molecules as compared to native Gαq model [80]. In that case, the R183Q mutation causes instability in inactivation of Gαq [80].…”

Section: Pathogenesis Of Pws/swsmentioning

confidence: 99%

“…In a silico protein-interaction model, it is proposed that the R183G mutation lost two hydrogen bonds between the Gαq and GDP molecules as compared to native Gαq model [80]. In that case, the R183Q mutation causes instability in inactivation of Gαq [80]. Therefore, the GNAQ (R183Q) likely plays a supportive role in maintaining the consecutive activation status of Gαq which has been activated by other stimuli or factors; while GNAQ (R183Q) alone is unlikely able to activate Gαq.…”

Section: Pathogenesis Of Pws/swsmentioning

confidence: 99%

The Pathogenesis of Port Wine Stain and Sturge Weber Syndrome: Complex Interactions between Genetic Alterations and Aberrant MAPK and PI3K Activation

Nguyen

Hochman

Mihm

et al. 2019

IJMS

100

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Port wine stain (PWS) is a congenital vascular malformation involving human skin. Approximately 15–20% of children a facial PWS involving the ophthalmic (V1) trigeminal dermatome are at risk for Sturge Weber syndrome (SWS), a neurocutaneous disorder with vascular malformations in the cerebral cortex on the same side of the facial PWS lesions. Recently, evidence has surfaced that advanced our understanding of the pathogenesis of PWS/SWS, including discoveries of somatic genetic mutations (GNAQ, PI3K), MAPK and PI3K aberrant activations, and molecular phenotypes of PWS endothelial cells. In this review, we summarize current knowledge on the etiology and pathology of PWS/SWS based on evidence that the activation of MAPK and/or PI3K contributes to the malformations, as well as potential futuristic treatment approaches targeting these aberrantly dysregulated signaling pathways. Current data support that: (1) PWS is a multifactorial malformation involving the entire physiological structure of human skin; (2) PWS should be pathoanatomically re-defined as “a malformation resulting from differentiation-impaired endothelial cells with a progressive dilatation of immature venule-like vasculatures”; (3) dysregulation of vascular MAPK and/or PI3K signaling during human embryonic development plays a part in the pathogenesis and progression of PWS/SWS; and (4) sporadic low frequency somatic mutations, such as GNAQ, PI3K, work as team players but not as a lone wolf, contributing to the development of vascular phenotypes. We also address many crucial questions yet to be answered in the future research investigations.

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“…For example, by sequencing the CARD15 gene in 30 children with Blau syndrome, Li et al identified a total of 10 mutations, of which 5 were unreported . In addition, Sturge‐Weber syndrome is a chimerism syndrome usually caused by the GNAQ gene mutations in some cells during development . For diseases caused by this type of chimerism mutation, the de novo mosaic disease‐causing mutations may be found by comparing the DNA sequences in diseased tissues with that in normal tissues (Figure B).…”

Section: Genome Analysis Strategies For Pediatric Diseasesmentioning

confidence: 99%

Application of genome analysis strategies in the clinical testing for pediatric diseases

Jin

Zhang

Hong

et al. 2018

Pediatric Investigation

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Next-generation sequencing (NGS) is being used in clinical testing. Government authorities in both China and the United States are overseeing the clinical application of NGS instruments and reagents. In addition, the US Association for Molecular Pathology and the College of American Pathologists have jointly released a guidance to standardize the analysis and interpretation of NGS data involved in clinical testing. At present, the analysis strategies and pipelines for NGS data related to the clinical detection of pediatric disease are similar to those used for adult diseases. However, for rare pediatric diseases without linkage to known genetic variants, it is currently difficult to detect the relevant pathogenic genes using NGS technology. Additionally, it is challenging to identify novel pathogenic genes of familial pediatric tumors. Therefore, characterization of the pathogenic genes associated with above diseases is important for the diagnosis and treatment of rare diseases in children. This article introduces the general pipelines for NGS data analyses of diseases and elucidates data analysis strategies for the pathogenic genes of rare pediatric diseases and familial pediatric tumors.

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Computational analysis for GNAQ mutations: New insights on the molecular etiology of Sturge-Weber syndrome

Cited by 33 publications

References 42 publications

Genetic syndromes with vascular malformations – update on molecular background and diagnostics

Genetic syndromes with vascular malformations – update on molecular background and diagnostics

The Pathogenesis of Port Wine Stain and Sturge Weber Syndrome: Complex Interactions between Genetic Alterations and Aberrant MAPK and PI3K Activation

Application of genome analysis strategies in the clinical testing for pediatric diseases

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