GJC2 promoter mutations causing Pelizaeus–Merzbacher-like disease

Gotoh, Leo; Inoue, Ken; Helman, Guy; Mora, Sara; Maski, Kiran; Soul, Janet S.; Bloom, Miriam; Evans, Sarah Helen; Goto, Yu‐ichi; Caldovic, Ljubica; Hobson, Grace M.; Vanderver, Adeline

doi:10.1016/j.ymgme.2013.12.001

Cited by 21 publications

(9 citation statements)

References 21 publications

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“…Substantial progress has been made in identifying genetic causes of CNS and PNS myelin disorders, such as Pelizaeus–Merzbacher and Charcot–Marie–Tooth disease (Nave and Trapp, ; Scherer and Wrabetz, ). Interestingly, noncoding mutations that are disease causing (or disease modifying) have been identified in Sox10 binding sites near the Connexin 32/GJB1, SH3TC2, Connexin 43/GJC2, and Myelin Protein Zero genes (Antonellis et al, ; Bondurand et al, ; Gotoh et al, ; Houlden et al, ; Meyer et al, ; Osaka et al, ; Schlierf et al, ; Brewer et al, ). Finally, understanding the coordination of glial differentiation by Sox10 and other factors will also elucidate stem cell approaches for glial development, which have employed Sox10 as a driver of glial differentiation (Najm et al, ; Wang et al, ; Yang et al, ).…”

Section: Discussionmentioning

confidence: 99%

Differential Sox10 genomic occupancy in myelinating glia

Lopez‐Anido

Sun

Koenning

et al. 2015

Glia

138

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Myelin is formed by specialized myelinating glia: oligodendrocytes and Schwann cells in the central and peripheral nervous systems, respectively. While there are distinct developmental aspects and regulatory pathways in these two cell types, myelination in both systems requires the transcriptional activator Sox10. Sox10 interacts with cell type-specific transcription factors at some loci to induce myelin gene expression, but it is largely unknown how Sox10 transcriptional networks globally compare between oligodendrocytes and Schwann cells. We used in vivo ChIP-Seq analysis of spinal cord and peripheral nerve (sciatic nerve) to identify unique and shared Sox10 binding sites and assess their correlation with active enhancers and transcriptional profiles in oligodendrocytes and Schwann cells. Sox10 binding sites overlap with active enhancers and critical cell type-specific regulators of myelination, such as Olig2 and Myrf in oligodendrocytes, and Egr2/Krox20 in Schwann cells. Sox10 sites also associate with genes critical for myelination in both oligodendrocytes and Schwann cells, and are found within super-enhancers previously defined in brain. In Schwann cells, Sox10 sites contain binding motifs of putative partners in the Sp/Klf, Tead, and nuclear receptor protein families. Specifically, siRNA analysis of nuclear receptors Nr2f1 and Nr2f2 revealed downregulation of myelin genes Mbp and Ndrg1 in primary Schwann cells. Our analysis highlights different mechanisms that establish cell type-specific genomic occupancy of Sox10, which reflects the unique characteristics of oligodendrocyte and Schwann cell differentiation.

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Section: Discussionmentioning

confidence: 99%

Differential Sox10 genomic occupancy in myelinating glia

Lopez‐Anido

Sun

Koenning

et al. 2015

Glia

138

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“…Most reported patients with GJC2 mutations present with symptoms similar to those found in PMD, and they include nystagmus, ataxia, dysarthria, impaired motor development, and progressive spasticity, accompanied by mild peripheral neuropathy (16). MRI findings in PMLD1 are consistent with diffuse hypomyelination found in PMD (17). In order to differentiate these two disorders brainstem auditory evoked potentials (BAEP) are proposed to be used.…”

Section: Pelizaeus-merzbacher-like Disease 1 (Gjc2 Related Disorder -mentioning

confidence: 98%

Hypomyelinating leukodystrophies — a molecular insight into the white matter pathology

Charzewska¹,

Wierzba

Iżycka‐Świeszewska

et al. 2016

Clinical Genetics

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Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. In the past various classification systems for HLDs have been used, based on imaging findings, clinical manifestation, and organelle-specific disorders. Here we present a molecular insight into HLDs based on a defect in specific gene engaged in myelination. We discuss recent findings on pathogenesis, clinical presentation, and imaging related to these disorders. We focus on HLDs that are in use in differential diagnostics of Pelizaeus-Merzbacher disease (PMD), with a special emphasis on Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition with delayed myelination due to thyroid transport disturbances. On the background of previously published patients we describe a proband initially considered as presenting with a severe PMD, whose diagnosis of AHDS due to a novel nonsense SLC16A2 mutation unraveled two previously undiagnosed generations of affected males who died in infancy from unexplained reasons. Since AHDS is found to be a relatively frequent cause of X-linked intellectual disability, we emphasize the need for determining the whole thyroid profile especially in hypotonic males with a delay of psychomotor development.

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“…Mutations in oligodendrocyte‐expressed Cx genes results in phenotypes indistinguishable from inherited hypomyelinating leukodystrophies, which are characterized by impairment of myelin sheath formation, inflammation, and sensorimotor deficits (Magnotti et al, ; May et al, ; Schiza et al, ). For example, a mutation in the Cx47 promoter results in Pelizaeus–Merzbacher‐like disease (Gotoh et al, ), while altered Cx32 expression leads to symptomology closely resembling Charcot‐Marie‐Tooth disease (Sargiannidou, Kim, Kyriakoudi, Eun, & Kleopa, ).…”

Section: Structure and Function Of Connexins And Pannexinsmentioning

confidence: 99%

Connexins and pannexins: At the junction of neuro‐glial homeostasis & disease

Lapato

Tiwari‐Woodruff

2017

J of Neuroscience Research

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In the central nervous system (CNS), connexin and pannexin gap junctions and hemichannels are an integral component of homeostatic neuronal excitability and synaptic plasticity. Neuronal connexin (Cx) gap junctions form electrical synapses across biochemically similar GABAergic networks, allowing rapid and extensive inhibition in response to principle neuron excitation. Glial Cx gap junctions link astrocytes and oligodendrocytes in the pan-glial network that is responsible for removing excitotoxic ions and metabolites. In addition, Cx gap junctions between glia help constrain excessive excitatory activity in neurons and facilitate astrocyte Ca2+ slow wave propagation. Pannexins (Panxs) do not form gap junctions in vivo, but Panx hemichannels participate in autocrine and paracrine gliotransmission alongside connexin hemichannels. ATP and other gliotransmitters released by Cx and Panx hemichannels maintain physiologic glutamatergic tone by strengthening synapses and mitigating aberrant high frequency bursting. Under pathological depolarizing and inflammatory conditions, gap junctions and hemichannels become dysregulated, resulting in aberrant neuronal firing and seizure. In this review, we present known contributions of Cxs and Panxs to physiologic neuronal excitation and explore how disruption of gap junctions and hemichannels lead to aberrant glutamatergic transmission, purinergic signaling, and seizures.

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GJC2 promoter mutations causing Pelizaeus–Merzbacher-like disease

Cited by 21 publications

References 21 publications

Differential Sox10 genomic occupancy in myelinating glia

Differential Sox10 genomic occupancy in myelinating glia

Hypomyelinating leukodystrophies — a molecular insight into the white matter pathology

Connexins and pannexins: At the junction of neuro‐glial homeostasis & disease

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