Relevance of <i>GJC2</i> promoter mutation in Pelizaeus‐Merzbacher–like disease

Combes, Patricia; Kammoun, Nadège; Monnier, Aurélie; Gonthier-Gueret, Céline; Giraud, G; Bertini, Enrico; Triki, Chahnez; Fakhfakh, Faïza; Boespflug‐Tanguy, Odile; Vaurs‐Barrière, Catherine

doi:10.1002/ana.22295

Cited by 16 publications

(14 citation statements)

References 5 publications

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“…[14] Patients with c.-167A>G mutations achieved walking with support (three cases) or autonomous walking (13 cases). [3, 5, 12, 13] though in most cases independent ambulation was ultimately lost. In one case data was insufficient to determine best motor function.…”

Section: Resultsmentioning

confidence: 99%

“…[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: 99%

“…[5] However, previous studies using the human GJC2 regulatory region did not show that the c.-167A>G mutation disrupts the SOX10-dependent transcription. [12]…”

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: Resultsmentioning

confidence: 99%

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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“…Our results add support for cvSI-1's role in host-defense and provide a plausible mechanism linking genetic variation to disease-resistance. In humans, genetic variations in promoter sequences that alter gene expression play a prominent role in increasing susceptibility to complex diseases [22,23]. This study provides an example in oysters.…”

Section: Discussionmentioning

confidence: 97%

Mutation in promoter region of a serine protease inhibitor confers Perkinsus marinus resistance in the eastern oyster (Crassostrea virginica)

He¹,

Yu²,

Bao³

et al. 2012

Fish & Shellfish Immunology

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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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Relevance of GJC2 promoter mutation in Pelizaeus‐Merzbacher–like disease

Cited by 16 publications

References 5 publications

GJC2 promoter mutations causing Pelizaeus–Merzbacher-like disease

GJC2 promoter mutations causing Pelizaeus–Merzbacher-like disease

Mutation in promoter region of a serine protease inhibitor confers Perkinsus marinus resistance in the eastern oyster (Crassostrea virginica)

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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