Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies

Warner, Laura E.; Mancías, Pedro; Butler, Ian J.; McDonald, Craig M.; Keppen, Laura Davis; Koob, K. G.; Lupski, James R.

doi:10.1038/ng0498-382

Cited by 457 publications

(351 citation statements)

References 28 publications

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“…Variants in EGR2 or MPZ genes (MIM159440, MIM129010) can lead to early onset of hypotonia, areflexia, distal muscle weakness, very slow nerve conduction velocities and hypomyelination process. 2,3 MPZ (Myelin Protein Zero) is the major structural protein of peripheral nerve myelin. The Egr2 transcription factor is critical for expression of myelin proteins and lipids.…”

Section: Introductionmentioning

confidence: 99%

Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy

Nizon¹,

Cogné²,

Vallat³

et al. 2016

Eur J Hum Genet

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Homozygous frameshift variants in CNTNAP1 have recently been reported in patients with arthrogryposis and abnormal axon myelination. In two brothers with severe congenital hypotonia and foot deformities, we identified compound heterozygous variants in CNTNAP1, reporting the first causative missense variant, p.(Cys323Arg). Motor nerve conductions were markedly decreased. Nerve microscopical lesions confirmed a severe hypomyelinating process and showed loss of attachment sites of the myelin loops on the axons, which could be a characteristic of Caspr loss-of-function. We discuss the pathophysiology of the myelination process and we propose to consider this disorder as a congenital hypomyelinating neuropathy.

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Section: Introductionmentioning

confidence: 99%

Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy

Nizon¹,

Cogné²,

Vallat³

et al. 2016

Eur J Hum Genet

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“…MPZ) (7) and others with known functions in Schwann cells (e.g. EGR2) (8), but many have poorly understood roles in Schwann cell biology. Furthermore, there is no effective treatment for CMT disease, which will likely require gene-and mutation-specific therapies.…”

Section: Introductionmentioning

confidence: 99%

SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locusMTMR2

Fogarty¹,

Brewer

Rodríguez-Molina³

et al. 2016

Hum. Mol. Genet.

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Schwann cells are the myelinating glia of the peripheral nervous system and dysfunction of these cells causes motor and sensory peripheral neuropathy. The transcription factor SOX10 is critical for Schwann cell development and maintenance, and many SOX10 target genes encode proteins required for Schwann cell function. Loss-of-function mutations in the gene encoding myotubularin-related protein 2 (MTMR2) cause Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe demyelinating peripheral neuropathy characterized by myelin outfoldings along peripheral nerves. Previous reports indicate that MTMR2 is ubiquitously expressed making it unclear how loss of this gene causes a Schwann cell-specific phenotype. To address this, we performed computational and functional analyses at MTMR2 to identify transcriptional regulatory elements important for Schwann cell expression. Through these efforts, we identified an alternative, SOX10-responsive promoter at MTMR2 that displays strong regulatory activity in immortalized rat Schwann (S16) cells. This promoter directs transcription of a previously unidentified MTMR2 transcript that is enriched in mouse Schwann cells compared to immortalized mouse motor neurons (MN-1), and is predicted to encode an N-terminally truncated protein isoform. The expression of the endogenous transcript is induced in a heterologous cell line by ectopically expressing SOX10, and is nearly ablated in Schwann cells by impairing SOX10 function. Intriguingly, overexpressing the two MTMR2 protein isoforms in HeLa cells revealed that both localize to nuclear puncta and the shorter isoform displays higher nuclear localization compared to the longer isoform. Combined, our data warrant further investigation of the truncated MTMR2 protein isoform in Schwann cells and in CMT4B1 pathogenesis.

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“…Recently, mutations in zinc finger domains of the EGR2 gene (also known as were associated with congenital hypomyelination (CHN) and CMT1. 24 EGR1, like EGR2, is an immediate early serum response gene. Both encode closely related zinc finger phosphoproteins that act as transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Genetic, cytogenetic and physical refinement of the autosomal recessive CMT linked to 5q31–q33: exclusion of candidate genes including EGR1

Guilbot

Ravisé

Bouhouche³

et al. 1999

Eur J Hum Genet

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Charcot-Marie-Tooth disease is an heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked and autosomal recessive. By homozygosity mapping, we have identified, in the 5q23-q33 region, a third locus responsible for an autosomal recessive form of demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricted the candidate region to a 4 cM interval. A physical map of the candidate region was established by screening YACs for microsatellites used for genetic analysis. Combined genetic, cytogenetic and physical mapping restricted the locus to a less than 2 Mb interval on chromosome 5q32. Seventeen consanguineous families with demyelinating ARCMT of various origins were screened for linkage to 5q31-q33. Three of these seventeen families are probably linked to this locus, indicating that the 5q locus accounts for about 20% of demyelinating ARCMT. Several candidate genes in the region were excluded by their position on the contig and/or by sequence analysis. The most obvious candidate gene, EGR1, expressed specifically in Schwann cells, mapped outside of the candidate region and no base changes were detected in two families by sequencing of the entire coding sequence.

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Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies

Cited by 457 publications

References 28 publications

Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy

Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy

SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locusMTMR2

Genetic, cytogenetic and physical refinement of the autosomal recessive CMT linked to 5q31–q33: exclusion of candidate genes including EGR1

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