Four common glomulin mutations cause two thirds of glomuvenous malformations ("familial glomangiomas"): evidence for a founder effect

Brouillard, Pascal; Ghassibé, Michella; Penington, Anthony; Boon, Laurence M.; Dompmartin, Anne; Temple, I K; Cordisco, Maria; Adams, Denise M.; Piette, F; Harper, John; Syed, Samira; Boralévi, F.; Taı̈eb, Alain; Danda, Sumita; Baselga, Eulàlia; Enjolras, O; Mulliken, John B.; Vikkula, Miikka

doi:10.1136/jmg.2004.024174

Cited by 130 publications

(90 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…4A). GLMN originally was identified as a gene responsible for familial glomuvenous malformations, a disorder that results in localized cutaneous vascular lesions because of loss-of-function mutations in the Glmn gene (45)(46)(47)(48). More recently, GLMN was characterized as a Cullin ring ligase inhibitor that blocks interaction with its ubiquitin-conjugating enzyme (E2) (49,50).…”

Section: Resultsmentioning

confidence: 99%

Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages

Suzuki

Mimuro

Kim

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

When nucleotide-binding oligomerization domain-like receptors (NLRs) sense cytosolic-invading bacteria, they induce the formation of inflammasomes and initiate an innate immune response. In quiescent cells, inflammasome activity is tightly regulated to prevent excess inflammation and cell death. Many bacterial pathogens provoke inflammasome activity and induce inflammatory responses, including cell death, by delivering type III secreted effectors, the rod component flagellin, and toxins. Recent studies indicated that Shigella deploy multiple mechanisms to stimulate NLR inflammasomes through type III secretion during infection. Here, we show that Shigella induces rapid macrophage cell death by delivering the invasion plasmid antigen H7.8 (IpaH7.8) enzyme 3 (E3) ubiquitin ligase effector via the type III secretion system, thereby activating the NLR family pyrin domain-containing 3 (NLRP3) and NLR family CARD domain-containing 4 (NLRC4) inflammasomes and caspase-1 and leading to macrophage cell death in an IpaH7.8 E3 ligase-dependent manner. Mice infected with Shigella possessing IpaH7.8, but not with Shigella possessing an IpaH7.8 E3 ligase-null mutant, exhibited enhanced bacterial multiplication. We defined glomulin/flagellar-associated protein 68 (GLMN) as an IpaH7.8 target involved in IpaH7.8 E3 ligase-dependent inflammasome activation. This protein originally was identified through its association with glomuvenous malformations and more recently was described as a member of a Cullin ring ligase inhibitor. Modifying GLMN levels through overexpression or knockdown led to reduced or augmented inflammasome activation, respectively. Macrophages stimulated with lipopolysaccharide/ATP induced GLMN puncta that localized with the active form of caspase-1. Macrophages from GLMN +/− mice were more responsive to inflammasome activation than those from GLMN +/+ mice. Together, these results highlight a unique bacterial adaptation that hijacks inflammasome activation via interactions between IpaH7.8 and GLMN.

show abstract

Section: Resultsmentioning

confidence: 99%

Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages

Suzuki

Mimuro

Kim

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…6 Researchers recently reported that a familial variant of glomus tumour had been linked to chromosome 1p21-22 and involved truncating mutations in the glomulin gene, which encoded a 68-kDa protein with unknown function. 9,10 Though, the cause of pain in glomus tumour is not clearly understood, several hypotheses have been made; presence of the capsule, which is sensitive to pressure, presence of mast cells releasing substances like heparin, histamine and 5-hydroxytryptamin which render the pressure and thermal receptors sensitive. 11 In addition, excessive dominance over the nerve of numerous non-myelinated nerve fibres that penetrate into glomus tumours has been suggested as a cause of pain.…”

Section: Etiopathogenesismentioning

confidence: 99%

Glomus tumours of the hand: Review of literature

Morey

Garg

Kotwal

2016

Journal of Clinical Orthopaedics and Trauma

134

View full text Add to dashboard Cite

“…Of the more than 30 mutations identified in more than 100 families, 11 account for .80% of patients (Brouillard, et al 2002(Brouillard, et al , 2005(Brouillard, et al , 2008O'Hagan et al 2006;P Brouillard, LM Boon, JB Mullikan, et al, unpubl.). The identification of the first somatic second-hit in a vascular anomaly, a 5-bp deletion in glomulin, provided evidence for a paradominant mode of inheritance (Brouillard et al 2002).…”

Section: Glomuvenous Malformationmentioning

confidence: 99%

Vascular Anomalies: From Genetics toward Models for Therapeutic Trials

Uebelhoer

Boon

Vikkula

2012

Cold Spring Harbor Perspectives in Medicine

View full text Add to dashboard Cite

Correspondence: miikka.vikkula@uclouvain.be Vascular anomalies are localized abnormalities that occur during vascular development. Several causative genes have been identified not only for inherited but also for some sporadic forms, and the molecular pathways involved are becoming understood. This gives us the opportunity to generate animals carrying the causative genetic defects, which we hope model the phenotype seen in human patients. These models would enable us not only to test known antiangiogenic drugs, but also to develop novel approaches for treatment, directly targeting the mutated protein or molecules implicated in the pathophysiological signaling pathways.

show abstract

Four common glomulin mutations cause two thirds of glomuvenous malformations ("familial glomangiomas"): evidence for a founder effect

Cited by 130 publications

References 28 publications

Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages

Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages

Glomus tumours of the hand: Review of literature

Vascular Anomalies: From Genetics toward Models for Therapeutic Trials

Contact Info

Product

Resources

About