A Novel Mutation (D305V) in the early growth response 2 gene is associated with severe Charcot-Marie-Tooth type 1 disease

Bellone, Emilia; Maria, Emilio Di; Soriani, S; Varese, Alessandra; D’Oria, Luisa; Ajmar, Franco; Mandich, Paola

doi:10.1002/(sici)1098-1004(199910)14:4<353::aid-humu17>3.0.co;2-4

Cited by 66 publications

(35 citation statements)

References 16 publications

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“…EGR2 gene that encodes a zinc-finger transcription factor plays an important role in the peripheral myelination. Mutations in EGR2 have been found in patients with CMT type 1, DSS and congenital hypomyelination (Warner et al, 1998;Bellone et al, 1999;Timmerman et al, 1999). NEFL gene encoding the neurofilament light chain plays an important role in axonal structure that includes an extensive fibrous network in the cytoplasm of the neuron.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2004

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“…By using these markers, we analyzed dnab e310 /dnab e310 , dnab G26 / dnab G26 , and dnab A23 /dnab A23 embryos for defects in axon outgrowth and targeting but found none (data not shown). The human NAB proteins have been indirectly implicated in peripheral glial development; several patients with congenital hypomyelinating neuropathies have been identified who have mutations in EGR2, a known hNAB1/hNAB2 binding partner (Botti et al, 1998;Warner et al, 1998;Bellone et al, 1999;Timmerman et al, 1999;Rogers et al, 2000). Therefore, we also examined glial development in dnab mutant Drosophila embryos by staining for RK2, a glia-specific homeodomain protein that is expressed in all CNS glia, with the exception of the midline glia.…”

Section: Dnab Function Is Required For Proper Formation Of Eve؉ Latermentioning

confidence: 99%

“…This finding suggests that NAB proteins might play a role in neuronal differentiation generally. In addition, the human NAB proteins have been implicated in regulating peripheral nerve myelination, because mutations in the NAB-interacting protein EGR2 have been identified in several patients with congenital hypomyelinating neuropathies (Botti et al, 1998;Warner et al, 1998;Bellone et al, 1999). At least one of these mutations occurs in the domain within EGR2 (R1 domain) required for NAB1/NAB2 binding.…”

Section: Introductionmentioning

confidence: 99%

Drosophila NAB (dNAB) is an orphan transcriptional co‐repressor required for correct CNS and eye development

Clements

Duncan

Milbrandt

2002

Developmental Dynamics

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The mammalian NAB proteins have been identified previously as potent co-repressors of the EGR family of zinc finger transcription factors. Drosophila NAB (dNAB), like its mammalian counterparts, binds EGR1 and represses EGR1-mediated transcriptional activation from a synthetic promoter. In contrast, dNAB does not bind the Drosophila EGR-related protein klumpfuss. dnab RNA is expressed exclusively in a subset of neuroblasts in the embryonic and larval central nervous system (CNS), as well as in several larval imaginal disc tissues. Here, we describe the creation of targeted deletion mutations in the dnab gene and the identification of additional, EMS-induced dnab mutations by genetic complementation analysis. Null alleles in dnab cause larval locomotion defects and early larval lethality (L1-L2). A putative hypomorphic allele in dnab instead causes early adult lethality due to severe locomotion defects. In the dnab -/-CNS, axon outgrowth/guidance and glial development appear normal; however, a subset of eve؉ neurons forms in reduced numbers. In addition, mosaic analysis in the eye reveals that dnab -/-clones are either very small or absent. Similarly, dNAB overexpression in the eye causes eyes to be very small with few ommatidia. These dramatic eye-specific phenotypes will prove useful for enhancer/suppressor screens to identify dnab-interacting genes. Developmental Dynamics 226:67-81, 2003.

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“…Mutations in SOX10 are associated with a complex syndrome involving peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease (Inoue et al, 2004). Dominant, neuropathy-associated mutations in EGR2 have been identified in all three zinc fingers of the DNA-binding domain (Warner et al, 1998;Bellone et al, 1999;Timmerman et al, 1999;Pareyson et al, 2000;Mikesova et al, 2005), and these mutations generally either impair or prevent DNA-binding Musso et al, 2001;Musso et al, 2003). Dominant mutants of EGR2 exert a dominant-negative effect on the activation of some endogenous target genes in Schwann cells by wild type EGR2 (Nagarajan et al, 2001;ArthurFarraj et al, 2006), with the most striking effects observed on Mpz.…”

Section: Introductionmentioning

confidence: 99%

Interactions of Sox10 and Egr2 in myelin gene regulation

et al. 2007

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Myelination in the PNS is accompanied by a large induction of the Myelin Protein Zero (Mpz) gene to produce the most abundant component in peripheral myelin. Analyses of knockout mice have shown that the EGR2/Krox20 and SOX10 transcription factors are required for Mpz expression. Our recent work has shown that the dominant EGR2 mutations associated with human peripheral neuropathies cause disruption of EGR2/SOX10 synergy at specific sites, including a conserved enhancer element in the first intron of the Mpz gene. Further investigation of Egr2/Sox10 interactions reveals that activation of the Mpz intron element by Egr2 requires both Sox10-binding sites. In addition, both Egr1 and Egr3 cooperate with Sox10 to activate this element, which indicates that this capacity is conserved among Egr family members. Finally, a conserved composite structure of Egr2/ Sox10-binding sites in the genes encoding Mpz, Myelin-associated glycoprotein (Mag), and Myelin Basic Protein (Mbp) genes was used to screen for similar modules in other myelin genes, revealing a potential regulatory element in the periaxin gene. Overall, these results elucidate a working model for developmental regulation of Mpz expression, several facets of which extend to regulation of other peripheral myelin genes.

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A Novel Mutation (D305V) in the early growth response 2 gene is associated with severe Charcot-Marie-Tooth type 1 disease

Cited by 66 publications

References 16 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

Drosophila NAB (dNAB) is an orphan transcriptional co‐repressor required for correct CNS and eye development

Interactions of Sox10 and Egr2 in myelin gene regulation

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