Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts

López-Hernández, Tania; Sirisi, Sònia; Capdevila-Nortes, Xavier; Montolio, Marisol; Fernández-Dueñas, Víctor; Scheper, Gert C.; Knaap, Marjo S. van der; Casquero, Pilar; Ciruela, Francisco; Ferrer, Isidre; Nunes, Virginia; Estévez, Raúl

doi:10.1093/hmg/ddr238

Cited by 82 publications

(115 citation statements)

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“…Expression of proteins allegedly associated or interacting with MLC113, 30, 31, 32, 33, 34 was evaluated by immunohistochemistry in 7‐month‐old mice. Compared to wild‐type animals, expression of the water channel aquaporin4 was redistributed along the cell bodies and processes of Glialcam ‐null astrocytes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…GlialCAM is a protein chaperone ensuring correct localization of MLC1 on the membrane of astrocytes 13. Recessive mutations in MLC1 and GLIALCAM lead to loss of MLC1 function causing indistinguishable clinical phenotype and brain MRI abnormalities in patients 12, 14.…”

Section: Discussionmentioning

confidence: 99%

“…GlialCAM shows a similar expression pattern, and is also expressed in oligodendrocytes 17, 19. Immunogold electron microscopy shows that GlialCAM and MLC1 co‐localize in astrocyte–astrocyte junctions at astrocytic endfeet 13. Both MLC1 and GlialCAM are associated with caveolae, which are important in compartmentalization of components involved in signal transduction, transport functions, endocytosis, and transcytosis 20, 21, 22, 23…”

Section: Introductionmentioning

confidence: 98%

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Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Bugiani

Dubey

Breur

et al. 2017

Ann Clin Transl Neurol

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ObjectiveMegalencephalic leukoencephalopathy with cysts (MLC) is a genetic infantile‐onset disease characterized by macrocephaly and white matter edema due to loss of MLC1 function. Recessive mutations in either MLC1 or GLIALCAM cause the disease. MLC1 is involved in astrocytic volume regulation; GlialCAM ensures the correct membrane localization of MLC1. Their exact role in brain ion‐water homeostasis is only partly defined. We characterized Glialcam‐null mice for further studies.MethodsWe investigated the consequences of loss of GlialCAM in Glialcam‐null mice and compared GlialCAM developmental expression in mice and men.Results Glialcam‐null mice had early‐onset megalencephaly and increased brain water content. From 3 weeks, astrocytes were abnormal with swollen processes abutting blood vessels. Concomitantly, progressive white matter vacuolization developed due to intramyelinic edema. Glialcam‐null astrocytes showed abolished expression of MLC1, reduced expression of the chloride channel ClC‐2 and increased expression and redistribution of the water channel aquaporin4. Expression of other MLC1‐interacting proteins and the volume regulated anion channel LRRC8A was unchanged. In mice, GlialCAM expression increased until 3 weeks and then stabilized. In humans, GlialCAM expression was highest in the first 3 years to then decrease and stabilize from approximately 5 years.Interpretation Glialcam‐null mice replicate the early stages of the human disease with early‐onset intramyelinic edema. The earliest change is astrocytic swelling, further substantiating that a defect in astrocytic volume regulation is the primary cellular defect in MLC. GlialCAM expression affects expression of MLC1, ClC‐2 and aquaporin4, indicating that abnormal interplay between these proteins is a disease mechanism in megalencephalic leukoencephalopathy with cysts.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Bugiani

Dubey

Breur

et al. 2017

Ann Clin Transl Neurol

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“…Several of the DEGs that enriched to the GO term "regulation of cellular processes" (Fig. 10B) play an important role in neuron survival, such as hepatic and glial cell adhesion molecule (HEPACAM, FC of 11, an axon protein that plays a role in neuron motility [92]), mitogen-activated protein (MAP) kinase 8 interacting protein 1 (JIP1, FC of 10, part of the MAP kinase signal transduction pathway in neurons [93]), FK056-binding protein 8 (FKBP8, FC of 9, inhibiting programmed cell death in neurons [94]), and BM88 antigen (FC of 10, involved in neuron differentiation [95]). of the downregulated DEGs that mapped to the GO processes "regulation of synaptic plasticity," "ion transport," "anion transport," and "endocytosis.…”

Section: Fig 7 Immunohistochemistry Gene Validation Ihc Staining Andmentioning

confidence: 99%

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Arnold

Girke

Sureshchandra

et al. 2016

J Virol

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Primary infection with varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, results in varicella. VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster. The relationship between VZV and its host during acute infection in the sensory ganglia is not well understood due to limited access to clinical specimens. Intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV) recapitulates the hallmarks of VZV infection in humans. We leveraged this animal model to characterize the host-pathogen interactions in the ganglia during both acute and latent infection by measuring both viral and host transcriptomes on days postinfection (dpi) 3, 7, 10, 14, and 100. SVV DNA and transcripts were detected in sensory ganglia 3 dpi, before the appearance of rash. CD4 and CD8 T cells were also detected in the sensory ganglia 3 dpi. Moreover, lung-resident T cells isolated from the same animals 3 dpi also harbored SVV DNA and transcripts, suggesting that T cells may be responsible for trafficking SVV to the ganglia. Transcriptome sequencing (RNA-Seq) analysis showed that cessation of viral transcription 7 dpi coincides with a robust antiviral innate immune response in the ganglia. Interestingly, a significant number of genes that play a critical role in nervous system development and function remained downregulated into latency. These studies provide novel insights into host-pathogen interactions in the sensory ganglia during acute varicella and demonstrate that SVV infection results in profound and sustained changes in neuronal gene expression. IMPORTANCEMany aspects of VZV infection of sensory ganglia remain poorly understood, due to limited access to human specimens and the fact that VZV is strictly a human virus. Infection of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, provides a robust model of the human disease. Using this model, we show that SVV reaches the ganglia early after infection, most likely by T cells, and that the induction of a robust innate immune response correlates with cessation of virus transcription. We also report significant changes in the expression of genes that play an important role in neuronal function. Importantly, these changes persist long after viral replication ceases. Given the homology between SVV and VZV, and the genetic and physiological similarities between rhesus macaques and humans, our results provide novel insight into the interactions between VZV and its human host and explain some of the neurological consequences of VZV infection. V aricella-zoster virus (VZV) is a neurotropic alphaherpesvirus and the causative agent of varicella (chickenpox) (1). VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster (shingles), a painful disease that affects almost 1 million individuals in the United States alone (2). VZV is transmitted through the inhalation of virus-laden saliva droplets or by direct contact with the infectious fluid from vesicles...

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“…Tipik klinik ve radyolojik bulguların varlığında tanı konulabilmektedir. Ancak, kesin tanı, sıklıkla 22q13.33 kromozomal bölgede bulunan megalensefalik lökoensefalopati ile subkortikal kistler 1 (MLC1) ve daha nadiren MLC2 mutasyonlarının gösterilmesi ile konur (2)(3)(4) …”

Section: Introductionunclassified

Three Siblings with Van der Knaap Disease

Sarsu¹,

Şahin²,

Işıkay³

et al. 2016

Haseki

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GirişVan der Knaap hastalığı, çok nadir görülen, makrosefali ile karakterize ilerleyici bir nörodejeneratif hastalıktır. Hastalık ilk kez 1995 yılında tanımlanmıştır ve otozomal resesif geçişli olması nedeniyle akraba evliliklerinin yaygın olduğu doğu toplumlarında daha fazla görülür (1). Erken çocukluk döneminde normal ya da normale yakın psikomotor gelişme olmasına rağmen, daha sonrasında epileptik nöbetler ve ataksik yürüyüş ortaya çıkmaktadır.Beyin manyetik rezonans görüntülemede (MRG) yaygın beyaz cevher tutulumu ve ön temporal bölgelerde daha belirgin olmak üzere subkortikal kistler ve yaygın ödem görülür. Tipik klinik ve radyolojik bulguların varlığında tanı konulabilmektedir. Ancak, kesin tanı, sıklıkla 22q13.33 kromozomal bölgede bulunan megalensefalik lökoensefalopati ile subkortikal kistler 1 (MLC1) ve daha nadiren MLC2 mutasyonlarının gösterilmesi ile konur (2-4).Ya z›fl maAd re si/Ad dressforCor res pon den ce:Sevgi Büyükbeşe Sarsu

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Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts

Cited by 82 publications

References 33 publications

Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Three Siblings with Van der Knaap Disease

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