EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy

Boerkoel, Cornelius F.; Takashima, Hiroshi; Bacino, Carlos A.; Daentl, Donna L.; Lupski, James R.

doi:10.1007/s100480100107

Cited by 59 publications

(39 citation statements)

References 27 publications

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“…The p.Arg359Trp mutation has been frequently reported in DSS patients with sporadic inheritance, however, our patients showed a CMT type 1 phenotype with autosomal dominant inheritance (Taroni et al, 1999;Timmerman et al, 1999;Boerkoel et al, 2001). It was not detected among the 105 healthy controls.…”

Section: Mutations In Egr2 and Neflmentioning

confidence: 56%

Mutational analysis ofPMP22, MPZ, GJB1, EGR2 andNEFL in Korean Charcot-Marie-Tooth neuropathy patients

et al. 2004

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We examined CMT1A duplication of 17p11.2-p12, mutations of PMP22, MPZ (P0), GJB1 (Cx32), EGR2 and NEFL genes in 57 Korean families with patients diagnosed as having Charcot-Marie-Tooth (CMT) disease. The CMT1A duplication was present in 53.6% of 28 CMT type 1 patients. In the 42 CMT families without CMT1A duplication, 10 pathogenic mutations were found in 9 families. The 10 mutations were not detected in 105 healthy controls. Seven mutations ( c.318delT (p.Ala106fs) in PMP22, c.352G>A (p.Asp118Asn), c.449-1G>T (3'-splice site), c.706A>G (p.Lys236Glu) in MPZ, c.408T>C (p.Val136Ala), c.502T>C (p.Cys168Arg) in GJB1, and c.1001T>C (p.Leu334Pro) in NEFL) were determined to be novel. The mutation frequencies of PMP22 and MPZ were similar to those found in several European populations, however, it appeared that mutations in GJB1 are less frequent in East Asian CMT patients than in European patients. We described the identified mutations and phenotype-genotype correlations based on nerve conduction studies.

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Section: Mutations In Egr2 and Neflmentioning

confidence: 56%

Mutational analysis ofPMP22, MPZ, GJB1, EGR2 andNEFL in Korean Charcot-Marie-Tooth neuropathy patients

et al. 2004

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“…These include congenital hypomyelinating neuropathy (CHN), as well as late-onset conditions such as CharcotMarie-Tooth disease (CMT) 1D subtype and Dejerine-Sottas syndrome (DSS) (Warner et al, 1998;Bellone et al, 1999;Timmerman et al, 1999;Pareyson et al, 2000;Boerkoel et al, 2001;Yoshihara et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Peripheral Myelin Maintenance Is a Dynamic Process Requiring ConstantKrox20Expression

Decker

Desmarquet-Trin-Dinh²,

Taillebourg³

et al. 2006

J. Neurosci.

148

151

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Onset of myelination in Schwann cells is governed by several transcription factors, including Krox20/Egr2, and mutations affecting Krox20 result in various human hereditary peripheral neuropathies, including congenital hypomyelinating neuropathy (CHN) and Charcot-Marie-Tooth disease (CMT). Similar molecular information is not available on the process of myelin maintenance. We have generated conditional Krox20 mutations in the mouse that allowed us to develop models for CHN and CMT. In the latter case, specific inactivation of Krox20 in adult Schwann cells results in severe demyelination, involving rapid Schwann cell dedifferentiation and increased proliferation, followed by an attempt to remyelinate and a block at the promyelinating stage. These data establish that Krox20 is not only required for the onset of myelination but that it is also crucial for the maintenance of the myelinating state. Furthermore, myelin maintenance appears as a very dynamic process in which Krox20 may constitute a molecular switch between Schwann cell myelination and demyelination programs.

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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%

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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EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy

Cited by 59 publications

References 27 publications

Mutational analysis ofPMP22, MPZ, GJB1, EGR2 andNEFL in Korean Charcot-Marie-Tooth neuropathy patients

Mutational analysis ofPMP22, MPZ, GJB1, EGR2 andNEFL in Korean Charcot-Marie-Tooth neuropathy patients

Peripheral Myelin Maintenance Is a Dynamic Process Requiring ConstantKrox20Expression

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

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