Mutations in connexin genes and disease

Pfenniger, Anna; Wohlwend, Annelise Isabelle; Kwak, Brenda R.

doi:10.1111/j.1365-2362.2010.02378.x

Cited by 141 publications

(133 citation statements)

References 108 publications

(162 reference statements)

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“…28 This is the first report of GJA5 variant in TOF patients and in general in CHDs. Various GJA5 defects other than p.Pro265Ser were previously associated with familial and sporadic atrial fibrillation.…”

Section: Discussionmentioning

confidence: 76%

A variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot

et al. 2012

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GJA5 gene (MIM no. 121013), localized at 1q21.1, encodes for the cardiac gap junction protein connexin 40. In humans, copy number variants of chromosome 1q21.1 have been associated with variable phenotypes comprising congenital heart disease (CHD), including isolated TOF. In mice, the deletion of Gja5 can cause a variety of complex CHDs, in particular of the cardiac outflow tract, corresponding to TOF in many cases. In the present study, we screened for mutations in the GJA5 gene 178 unrelated probands with isolated TOF. A heterozygous nucleotide change (c.793C4T) in exon 2 of the gene leading to the p.Pro265Ser variant at the carboxyl-terminus of the protein was found in two unrelated sporadic patients, one with classic anatomy and one with pulmonary atresia. This GJA5 missense substitution was not observed in 1568 ethnically-matched control chromosomes. Immunofluorescent staining and confocal microscopy revealed that cells expressing the mutant protein form sparse or no visible gap-junction plaques in the region of cell-cell contact. Moreover, analysis of the transfer of the gap junction permanent tracer lucifer yellow showed that cells expressing the mutant protein have a reduced rate of dye transfer compared with wild-type cells. Finally, use of a zebrafish model revealed that microinjection of the GJA5-p.Pro265Ser mutant disrupts overall morphology of the heart tube in the 37% (22/60) of embryos, compared with the 6% (4/66) of the GJA5 wild-type-injected embryos. These findings implicate GJA5 gene as a novel susceptibility gene for TOF.

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Section: Discussionmentioning

confidence: 76%

A variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot

et al. 2012

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“…Many mutants have reduced or absent channel function or form channels/ hemichannels with altered gating or permeability (2,3,(5)(6)(7)(8)(9). Many mutants show alterations in their cellular behaviors including impaired trafficking or degradation that can lead to accumulation of the abnormal protein (2,3,(5)(6)(7)(8)(9). Several of the CX46 and CX50 mutants linked to cataracts have been thoroughly studied (10 -17).…”

Section: Connexins (Cxs)mentioning

confidence: 99%

“…1). Identification of connexin mutants has linked alterations of connexins and their functions to human diseases including demyelinating neuropathies, oculodentodigital dysplasia, skin disorders, deafness, arrhythmias, and cataracts (2)(3)(4)(5)(6)(7)(8)(9).…”

Section: Connexins (Cxs)mentioning

confidence: 99%

A Connexin50 Mutant, CX50fs, That Causes Cataracts Is Unstable, but Is Rescued by a Proteasomal Inhibitor

Minogue

Beyer

Berthoud

2013

Journal of Biological Chemistry

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Background:The mechanism by which CX50fs, a mutant connexin50 containing a frameshift after amino acid 255, causes cataracts is unknown. Results: CX50fs was unstable in HeLa cells, but epoxomicin treatment restored gap junction abundance and intercellular communication. Conclusion: CX50fs undergoes enhanced endoplasmic reticulum-associated proteasomal degradation leading to decreased function. Significance: The results suggest protease inhibition as a novel therapeutic approach to treat connexin mutant-associated diseases.

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“…Most Cx genes have a similar structure and contain the protein coding region as a single exon (Willecke et al, 2002;Söhl and Willecke, 2003;2004;Pfenniger et al, 2011). Cxs were initially denoted according to the tissue of origin or the apparent size of a polypeptide as determined by SDS-PAGE.…”

Section: Mammalian Connexinsmentioning

confidence: 99%