Disrupted <i>SOX10</i> regulation of <i>GJC2</i> transcription causes Pelizaeus‐Merzbacher‐like disease

Osaka, Hitoshi; Hamanoue, Haruka; Yamamoto, Ryo; Nezu, Atsuo; Sasaki, Megumi; Saitsu, Hirotomo; Kurosawa, Kenji; Shimbo, Hiroko; Matsumoto, Naomichi; Inoue, Ken

doi:10.1002/ana.22022

Cited by 39 publications

(45 citation statements)

References 21 publications

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“…[2, 4, 6-11] An additional mutation, c.-167A>G, was identified in the putative promoter region in individuals with the phenotype of PMLD. [3, 5, 12, 13] This promoter mutation was first identified in the homozygous state, has now been reported in 15 individuals from 5 families,[3, 5, 12, 13] and has additionally been found in two patients[12] in the heterozygous state with another previously published mutation[7] within the coding sequence of GJC2. There is evidence suggesting that some c.-167A>G cases arose from a single founder[3, 13] and this mutation is thought to account for nearly a third of GJC2 -PMLD phenotypes.…”

Section: Introductionmentioning

confidence: 98%

“…[3, 4] Mutation of GJC2 does not allow Cx47 to reach the membrane, resulting in loss of function. [5] Additionally, the GJC2 promoter region contains SOX10 transcriptional factor binding sites, which allow for SOX10 to play a role in myelin formation. [5]…”

Section: Introductionmentioning

confidence: 99%

“…[5] Additionally, the GJC2 promoter region contains SOX10 transcriptional factor binding sites, which allow for SOX10 to play a role in myelin formation. [5]…”

Section: Introductionmentioning

confidence: 99%

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GJC2 promoter mutations causing Pelizaeus–Merzbacher-like disease

Gotoh

Inoue

Helman

et al. 2014

Molecular Genetics and Metabolism

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Objective Pelizaeus-Merzbacher-like disease is a rare hypomyelinating leukodystrophy caused by autosomal recessive mutations in GJC2, encoding a gap junction protein essential for production of a mature myelin sheath. A previously identified GJC2 mutation (c.-167G>A) in the promoter region is hypothesized to disrupt a putative SOX10 binding site; however, the lack of additional mutations in this region and contradictory functional data have limited the interpretation of this variant. Methods We describe two independent Pelizaeus-Merzbacher-like disease families with a novel promoter region mutation and updated in vitro functional assays. Results A novel GJC2 mutation (c.-170G>A) in the promoter region was identified in Pelizaeus-Merzbacher-like disease patients. In vitro functional assays using human GJC2 promoter constructs demonstrated that this mutation and the previously described c.-167G>A mutation similarly diminished the transcriptional activity driven by SOX10 and the binding affinity for SOX10. Interpretation These findings support the role of GJC2 promoter mutations in Pelizaeus-Merzbacher-like disease. GJC2 promoter region mutation screening should be included in the evaluation of patients with unexplained hypomyelinating leukodystrophies.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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GJC2 promoter mutations causing Pelizaeus–Merzbacher-like disease

Gotoh

Inoue

Helman

et al. 2014

Molecular Genetics and Metabolism

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“…Such as apparent contradiction may be explained by the fact that carcinogenesis and CJIC are linked, but that this is not a monofactorial or unidirectional relationship: there are other factors contributing to carcinogenesis -and there are stages in carcinogenesis that may benefit from increased Cx levels and an enhanced GJIC, such as invasion and metastasis. For these reasons, connexins were recently characterized as conditional tumor suppressor [34] . miRNAs are able to regulate gap junction proteins which is critical for cardiac rhythm.…”

Section: "Micrornasmentioning

confidence: 99%

MicroRNAs as regulators of connexin-43 expression

Yang²,

Zhang³

et al. 2016

Cancer Cell Microenviron

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Posttranscriptional regulation of the biosynthesis of connexins, the building blocks of gap junctional channels, may occur by modulation of connexin mRNA stability and translation. To date, few RNA binding proteins and micro-RNAs (miRNAs) affecting connexin expression are known. In recent years, it has become clear that epigenetic processes are also essentially involved in connexin gene expression. In this review, we summarize recent knowledge on regulation of connexin expression by transcription factors and epigenetic mechanisms including microRNA.

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“…3 To date, 25 different GJC2 mutant alleles, harbouring 9 missense, 10 frameshift, 3 nonsense, 1 microinsertion and 1 regulatory mutations have been reported in 54 PMLD1 patients belonging to 32 families. [4][5][6][7][8][9][10][11][12][13] In addition, another GJC2 missense mutation causing a milder phenotype, the spastic paraplegia autosomal recessive type 44 (SPG44) (MIM# 613206), has been reported in three members of a single family. 14 These findings suggest that this gene may give rise to a spectrum of disorders with different severity, in analogy with the PLP1 gene.…”

Section: Introductionmentioning

confidence: 99%

Expanded spectrum of Pelizaeus–Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form

et al. 2012

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Homozygous or compound heterozygous mutations in the GJC2 gene, encoding the gap junction protein connexin47 (Cx47), cause the autosomal recessive hypomyelinating Pelizaeus-Merzbacher-like disease (PMLD1, MIM# 608804). Although clinical and neuroradiological findings resemble those of the classic Pelizaeus-Merzbacher disease, PMLD patients usually show a greater level of cognitive and motor functions. Unpredictably a homozygous missense GJC2 mutation (p.Glu260Lys) was found in a patient presenting with a very severe clinical picture characterised by congenital nystagmus and severe neurological impairment. Also magnetic resonance imaging was unusually severe, showing an abnormal supra-and infratentorial white matter involvement extending to the spinal cord. The novel p.Glu260Lys (c.778G4A) mutation, occurring in a highly conserved motif (SRPTEK) of the Cx47 extracellular loop-2 domain, was predicted, by modelling analysis, to break a 'salt bridge network', crucial for a proper connexin-connexin interaction to form a connexon, thus hampering the correct formation of the connexon pore. The same structural analysis, extended to the previously reported missense mutations, predicted that most changes were expected to have less severe impact on protein functions, correlating with the mild PMLD1 form of the patients. Our study expands the spectrum of PMLD1 and provides evidence that the extremely severe clinical and neuroradiological PMLD1 form of our patient likely correlates with the predicted impairment of gap junction channel assembly resulting from the detrimental effect of the new p.Glu260Lys mutant allele on Cx47 protein.

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Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus‐Merzbacher‐like disease

Cited by 39 publications

References 21 publications

GJC2 promoter mutations causing Pelizaeus–Merzbacher-like disease

GJC2 promoter mutations causing Pelizaeus–Merzbacher-like disease

MicroRNAs as regulators of connexin-43 expression

Expanded spectrum of Pelizaeus–Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form

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