Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination

Wolf, Nicole I.; Cundall, Maria; Rutland, Paul; Rosser, Elisabeth; Surtees, Robert; Benton, Sarah; Chong, W.K.; Malcolm, Sue; Ebinger, Friedrich; Bitner‐Glindzicz, Maria; Woodward, Karen

doi:10.1007/s10048-006-0062-0

Cited by 43 publications

(46 citation statements)

References 11 publications

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“…Mutations are designated according to current guidelines of international mutation nomenclature. Designation of the mutation p.P305RfsX155 6 and of the mutation p. P73AfsX35 9 was changed according to current guidelines of mutation nomenclature.…”

Section: Electrophysiological Studiesmentioning

confidence: 99%

“…Until now 23 different GJA12/GJC2 mutations have been reported. [3][4][5][6][7][8][9] Gap junctions (GJs) are specialized channels between apposed cells allowing direct metabolic and electrical communication between most cell types in mammalian tissues by passive diffusion of molecules smaller than 1000Da. This gap junction intercellular communication (GJIC) has an important role in essential cellular processes, such as development, proliferation, differentiation, and cell death.…”

Section: Introductionmentioning

confidence: 99%

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Pelizaeus–Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction

et al. 2010

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Autosomal recessive mutations in the GJA12/GJC2 gene encoding the gap junction protein connexin47 (CÂ47) cause a form of Pelizaeus-Merzbacher-like disease (PMLD) with hypomyelination, nystagmus, impaired psychomotor development and progressive spasticity. We investigated the functional consequences of four CÂ47 missense mutations (G149S, G236R, T265A, and T398I) and one CÂ47 complex mutation (A98G_V99insT) by immunoblot analysis and immunocytochemistry in transfected communication-incompetent HeLa cells and in OLI-neu cells. All studied CÂ47 mutants, except G236R, generated stable proteins in transfected HeLa cells and OLI-neu cells. The mutants T265A and A98G_V99insT were retained in the ER, T398I formed gap junctional plaques at the plasma membrane, and G149S showed both, structures at the plasma membrane and ER localization. Two-microelectrode voltage clamp analyses in Xenopus laevis oocytes injected with wild-type and mutant CÂ47 cRNA revealed reduced hemichannel currents for G236R, T265A, and A98G_V99insT. In contrast, T398I revealed hemichannel currents comparable to wild-type. For CÂ47 mutant T398I, our results indicate a defect in hemichannel function, whereas CÂ47 mutants G149S, G236R, T265A, and A98G_V99insT are predicted to result in a loss of CÂ47 hemichannel function. Thus, PMLD is likely to be caused by two different disease mechanisms: a loss of function and a dysfunction.

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Section: Electrophysiological Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pelizaeus–Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction

et al. 2010

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“…PMD and Pelizaeus- Merzbacher-like disease (PMLD) have an analogous clinical and neuroradiological syndrome. PMLD is caused by recessive mutations in the connexin 47 (Cx47 or GJC2) gene [22,23,24,25], which codes for the GJ protein Cx47.…”

Section: Introductionmentioning

confidence: 99%

Changes in Object Recognition and Anxiety-Like Behaviour in Mice Expressing a Cx47 Mutation That Causes Pelizaeus-Merzbacher-Like Disease

Zlomuzica¹,

Tress²,

Binder³

et al. 2012

Dev Neurosci

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Pelizaeus-Merzbacher-like disease is characterized by impaired psychomotor development, ataxia, progressive spasticity and mental retardation. It is induced by mutations in the gap junction gene GJC2 that encodes for the gap junction protein connexin 47. Mice bearing a human Cx47M283T missense mutation have been generated as a transgenic mouse model of Pelizaeus-Merzbacher-like disease. Homozygous expression of the mutant connexin 47 gene in oligodendrocytes resulted in a complex and variable neuropathologic phenotype, which was associated with impairments in motor coordination in juvenile, but not adult mice. In the present study, we have investigated anxiety-like behaviour and spatial working memory in juvenile (P23) and adult (3-month-old) Cx47M282T mutant mice. Adult Cx47M282T mice were also evaluated in terms of neuromotor functions and in the novel object recognition test. Juvenile Cx47M282T mutant mice exhibited an increase in anxiety-like behaviour in the open field test, but no changes in spatial working memory performance. No significant changes in anxiety-like behaviour, spatial working memory or neuromotor functions were observed in the adult Cx47M282T mutant mice. However, novel object recognition was significantly impaired in adult Cx47M282T mice. Our results suggest that the expression of the human Cx47M282T mutation in the mouse causes changes in anxiety-like behaviour in juvenile and novel object recognition impairments in adult mice. It appears that the distortion of panglial gap junction coupling in white and grey matter tissue in the Cx47M282T mice is associated with a complex age-dependent behavioural phenotype including changes in psychomotor, emotional and memory functions.

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“…Mutations in the GJA12 gene as the cause for PMLD could be confirmed by other research groups [Bugiani et al, 2006;Salviati et al, 2007;Wolf et al, 2007].…”

Section: Introductionmentioning

confidence: 75%

Analysis of human alternative first exons and copy number variation of the GJA12 gene in patients with Pelizaeus–Merzbacher‐like disease

Ruf

Uhlenberg

2008

American J of Med Genetics Pt B

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Pelizaeus-Merzbacher-like disease (PMLD) is a heterogeneous disease with primary hypomyelination of the central nervous system. Only the minority of patients have mutations in the coding region of the GJA12 gene encoding gap junction protein alpha 12, a subunit of intercellular channels highly expressed by oligodendrocytes, the myelin forming cells of the central nervous system. No other gene has been found so far to be mutated in PMLD besides GJA12. We therefore extended the mutational screening in the GJA12 gene, searched for alternative first exons-as described in mice-determined the human 5'-end of the gene, screened therein for mutations and analyzed for copy number variations of the GJA12 gene in 14 patients with PMLD. Unlike in mice we did not find alternative first exons but detected a unique 79 bp first exon in human adolescent brain and spinal cord. No mutation in this non-coding region was found in our cohort. Copy number variation of the GJA12 gene was assessed by real-time PCR TaqMan gene expression technology, but neither patient showed an aberrant copy number. These data confirm that GJA12 alterations are a rare cause of PMLD-even after extending the screening for copy number variation and for mutations in the non-coding region of GJA12. Full genome scans in informative families and further screenings of candidate genes are feasible approaches to elucidate the genetic background of the majority of patients with PMLD.

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Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination

Cited by 43 publications

References 11 publications

Pelizaeus–Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction

Pelizaeus–Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction

Changes in Object Recognition and Anxiety-Like Behaviour in Mice Expressing a Cx47 Mutation That Causes Pelizaeus-Merzbacher-Like Disease

Analysis of human alternative first exons and copy number variation of the GJA12 gene in patients with Pelizaeus–Merzbacher‐like disease

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