Functional, histopathologic and natural history study of neuropathy associated with EGR2 mutations

Szigeti, Kinga; Wiszniewski, Wojciech; Saifi, Gulam Mustafa; Sherman, Diane L.; Süle, Norbert; Adesina, Adekunle M.; Mancías, Pedro; Papasozomenos, Sozos Ch.; Miller, Geoffrey; Keppen, Laura Davis; Daentl, Donna L.; Brophy, Peter; Lupski, James R.

doi:10.1007/s10048-007-0094-0

Cited by 45 publications

(39 citation statements)

References 23 publications

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“…38 CMT is characterized by phenotypic variability even within patients carrying the same mutations. 39,40 However, overall severity varies according to the causative gene and type of mutation.…”

Section: Discussionmentioning

confidence: 99%

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

et al. 2011

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To study the genetic background of Japanese Charcot-Marie-Tooth disease (CMT) patients, we analyzed qualitative and quantitative changes in the disease-causing genes mainly by denaturing high performance liquid chromatography and multiplex ligation-dependent probe analysis in 227 patients with demyelinating CMT and 127 patients with axonal CMT. In demyelinating CMT, we identified 53 patients with PMP22 duplication, 10 patients with PMP22 mutations, 20 patients with MPZ mutations, eight patients with NEFL mutations, 19 patients with GJB1 mutations, one patient with EGR2 mutation, five patients with PRX mutations and no mutations in 111 patients. In axonal CMT, we found 14 patients with MFN2 mutations, one patient with GARS mutation, five patients with MPZ mutations, one patient with GDAP1 mutation, six patients with GJB1 mutations and no mutations in 100 patients. Most of the patients carrying PMP22, MPZ, NEFL, PRX and MFN2 mutations showed early onset, whereas half of the patients carrying PMP22 duplication and all patients with GJB1 or MPZ mutations showing axonal phenotype were adult onset. Our data showed that a low prevalence of PMP22 duplication and high frequency of an unknown cause are features of Japanese CMT. Low prevalence of PMP22 duplication is likely associated with the mild symptoms due to genetic and/or epigenetic modifying factors.

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Section: Discussionmentioning

confidence: 99%

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

et al. 2011

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“…In accordance, various Krox20 mutations have been associated with human peripheral neuropathies, including different forms of Charcot-Marie-Tooth disease, Dejerine-Sottas Syndrome, and congenital hypomyelinating neuropathy (CHN) (Warner et al, 1998;Bellone et al, 1999;Timmerman et al, 1999;Pareyson et al, 2000;Boerkoel et al, 2001;Yoshihara et al, 2001;Szigeti et al, 2007). Whereas most of these mutations affect the DNA binding domain, another type corresponds to the specific replacement of the isoleucine at position 268 (Warner et al, 1998;Szigeti et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…This is an early and very severe peripheral neuropathy that has been classified as congenital hypomyelinating neuropathy (Warner et al, 1998). It leads to a near complete loss of myelin sheath with severe reduction of MBP immunoreactivity (Szigeti et al, 2007), like in the Krox20 I268F/I268F mice. In both cases, the mutation appears recessive.…”

Section: A Novel Model For Peripheral Neuropathymentioning

confidence: 99%

“…Whereas most of these mutations affect the DNA binding domain, another type corresponds to the specific replacement of the isoleucine at position 268 (Warner et al, 1998;Szigeti et al, 2007). This amino acid has been shown to be required for the interaction of the closely related factor Egr1/ Krox24 with its cofactors Nab1 and Nab2 (Swirnoff et al, 1998;Warner et al, 1999), suggesting that this interaction is also essential for Krox20 function.…”

Section: Introductionmentioning

confidence: 99%

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Disruption of Krox20-Nab Interaction in the Mouse Leads to Peripheral Neuropathy with Biphasic Evolution

Desmazières¹,

Decker²,

Vallat³

et al. 2008

Journal of Neuroscience

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Krox20/Egr2 is a zinc finger transcription factor that plays essential roles in several developmental processes, including peripheral nervous system myelination by Schwann cells, where it acts as a master gene regulator. Krox20 is known to interact with cofactors of the Nab family and a mutation affecting isoleucine 268, which prevents this interaction, has been shown to result in congenital hypomyelinating neuropathy in humans. To further investigate the role of this interaction, we have introduced such a mutation, Krox20 I268F, in the mouse germ line. Clinical, immunohistochemical, and ultrastructural analyses of the homozygous mutants reveal that they develop a severe hypomyelination phenotype that mimics the human syndrome. Furthermore, a time-course analysis of the disease indicates that it follows a biphasic evolution, the hypomyelination phase being followed by a dramatic demyelination. Although for the regulation of most analyzed Krox20 target genes the mutation behaves as a loss of function, this is not the case for a few of them. This differential effect indicates that the molecular function of the Krox20 -Nab interaction is target dependent and might explain the degradation of the residual myelin, because of imbalances in its composition. In conclusion, this work provides a novel and useful model for severe human peripheral neuropathies.

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“…The CCL1-CCR8 axis is also relevant in other diseases, including multiple sclerosis and cancer, yet a link to Egr2 remains unclear (42,43). Interestingly, however, Egr2 is required for the expression of a myriad of myelinating genes in neurons (31), and mutations in Egr2 are associated with CharcotMarie-Tooth disease, a condition in which impaired Egr2 DNA binding results in nerve demyelination (44), bearing phenotypic similarities to multiple sclerosis, although seemingly mechanistically distinct.…”

Section: Discussionmentioning

confidence: 99%

Mast Cell FcεRI-Induced Early Growth Response 2 Regulates CC Chemokine Ligand 1–Dependent CD4+ T Cell Migration

MacNeil

Junkins

et al. 2013

The Journal of Immunology

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Mast cells are well positioned in host tissue for detecting environmental signals, including allergens, leading to activation of the high-affinity IgE receptor FcεRI, and initiating a signaling cascade that perpetuates the production of biologically potent mediators, including chemokines. We have identified a novel target of mast cell FcεRI activity in the transcription factor early growth response 2 (Egr2) and sought to characterize its function therein. Egr2 was transiently activated following FcεRI-mediated signaling, targeted the promoter of the chemokine CCL1, and was critical for allergen-induced mast cell CCL1 production. Egr2-deficient mast cells were incapable of directing CD4+ T cell migration via the CCL1–CCR8 axis. In a model of allergic asthma, reconstitution of mast cell–deficient mice with Egr2-deficient mast cells demonstrated that mast cell Egr2 was essential for migration of CD4+ T cells to the inflamed lung. These findings position Egr2 as a critical regulator of mast cell–directed CD4+ T cell migration.

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Functional, histopathologic and natural history study of neuropathy associated with EGR2 mutations

Cited by 45 publications

References 23 publications

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

Disruption of Krox20-Nab Interaction in the Mouse Leads to Peripheral Neuropathy with Biphasic Evolution

Mast Cell FcεRI-Induced Early Growth Response 2 Regulates CC Chemokine Ligand 1–Dependent CD4+ T Cell Migration

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