Disease relevance of GJA5

• In contrast, in humans suffering from atrial fibrillation (AF), the content in Cx40 can be enhanced while Cx43 was unaltered, although in several other studies, other changes of the cardiac connexins were found, which might be related to the type of AF [1].
• A decrease in Cx43 with a concomitant increase in Cx40 has been found in end-stage failing hearts, while in renovascular hypertension, an increase in Cx43 has been described [1].
• Coinheritance of Cx40 polymorphisms is a possible genetic factor that modifies the clinical manifestation of this inherited arrhythmia [2].
• No mRNA expression of Cx37, Cx40 or Cx45 in either mesothelioma tumour cells or the primary mesothelial cells was detected [3].
• METHODS: A communication-deficient human hepatoma cell line (SKHep1) was stably transfected with human Cx40 cDNA and the properties of Cx40 gap junctions channels and their modulation by cAMP were analyzed using immunocytochemistry, Western blotting, dual patch clamp, and dye coupling [4].

High impact information on GJA5

• Based on the disease phenotype and map location we speculate that gap junction protein connexin 40 is a candidate for mutations that result in conduction system disease and dilated cardiomyopathy [5].
• Microinjection of Cx40 cRNA into Xenopus oocytes induced functional cell-to-cell channels between pairs [6].
• Based on both protein and nucleotide sequence, mouse Cx40 is more closely related to mouse Cx43 (alpha subgroup of connexins) than to mouse Cx32 (beta subgroup) [6].
• Transfection of mouse Cx40 DNA, under control of the SV-40 early promoter, into coupling-deficient human HeLa or SK-Hep-1 cells resulted in expression of the expected transcript and restoration of fluorescent dye transfer in transfected clones [6].
• The coding region of Cx40 is uninterrupted by introns and is detected as a single copy gene in the mouse genome [6].

Biological context of GJA5

• Physical mapping of the human connexin 40 (GJA5), flavin-containing monooxygenase 5, and natriuretic peptide receptor a genes on 1q21 [7].
• Together, these results suggest that gap junctions composed particularly of Cx40 channels are required for the proliferation of EVT cells in anchoring cell columns, and that a loss of GJIC contributes to differentiation to the invasive EVT phenotype [8].
• Cx40 expression is prominent in the anchoring column throughout the first trimester of pregnancy (6-14 weeks gestation) [8].
• Cx40 antisense treatment also resulted in the abolishment of outgrowth EVT cell proliferation (as determined by Ki67 immunostaining) [8].
• Cx40 genotypes were determined by DNA sequencing [9].

Anatomical context of GJA5

• Cx40 is present between endothelial cells of vessels and glomeruli, as well as between renin-secreting cells, the modified smooth muscle cells which form the wall of the terminal part of afferent arterioles [10].
• We used the polymerase chain reaction and genomic cloning to isolate DNA encoding the gap junction proteins human connexin40 (Cx40) and connexin45 (Cx45) [11].
• In contrast, Cx40 staining in the ventricle was confined to mural coronary arteries, apparently in endothelial cells, whereas in the atrium Cx40 staining at myocyte junctions was abundant.(ABSTRACT TRUNCATED AT 250 WORDS)[12]
• Cx40 levels varied between chambers in the order right atrium >left atrium >/= right ventricle approximately left ventricle [13].
• Cx40 mRNA was approximately 5-fold more abundant in samples from fetal hearts than in hearts of children or adults [12].

Associations of GJA5 with chemical compounds

• Stimulation in vitro of T and B lymphocytes with phytohaemagglutinin (PHA) and lipopolysaccharide (LPS), respectively, increased Cx40 and Cx43 protein expression [14].
• Regarding the role of calcium, the content in both Cx40 and Cx43 was decreased in cultured neonatal rat cardiomyocytes after 24 h administration of 100 nM verapamil [1].
• When cytotrophoblastic cells were cultured on Matrigel for 2 days, alpha5beta1 integrin expression was observed concomitant with the presence of Cx40 mRNA and of Cx40 protein between the cells [15].
• Affinity purification of material solubilized by Triton X-100 from cells co-expressing mutant Cx43 or mutant Cx40 with wild-type Cx40, Cx43 or Cx26 showed that introducing the mutations did not affect the compatibility or incompatibility of these proteins for heteromeric mixing [16].
• Unlike wild-type Cx40, Cx40E12S,E13G channels were insensitive to block by 2 mM spermine [16].

Regulatory relationships of GJA5

• In this study we show that decidua conditioned media (DCM) downregulate Connexin 40 (Cx40) expression in extravillous trophoblast (EVT) outgrowths and can promote EVT differentiation to the invasive phenotype resulting in switching of integrin and EGF receptor expression [17].

Other interactions of GJA5

• Immunostaining revealed typical punctate staining for Cx43 and Cx40 along regions of intimate cell-to-cell contact between hMSCs [18].
• Cx45 was detectable only at very low levels, with a trend toward higher levels in the atria than the ventricles in a pattern similar to Cx40 [13].
• Under control conditions, Cx43, Cx40, and Cx37 protein and mRNA were present in HUVEC [19].
• Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms [2].
• If TNF-alpha was removed from the medium, Cx37 and Cx40 expression was restored within 24 h [19].

Analytical, diagnostic and therapeutic context of GJA5

• Northern analysis of adult human right atrial appendages revealed abundant Cx40 mRNA, thus suggesting that the greater amount of Cx40 signal seen on Northern blots from fetal hearts could have been attributable to atrial contributions [12].
• Immunohistochemistry with connexin-specific antibodies confirmed that Cx40, Cx43, and Cx45 all localized to intercalated disk regions in frozen sections of human left ventricle [11].
• Western blot analysis also demonstrated the presence of Cx40 and Cx43 proteins in T and B lymphocytes in a manner coincidental to the mRNA detection [14].
• Cx40, Cx43, and Cx45 were visualized by immunofluorescence at points of contact between adjacent cells [20].
• We screened 505 unrelated CHD cases for deletions or duplications of the Cx40 gene (GJA5) by real-time quantitative PCR, in order to determine whether altered copy number of this gene may be associated with a cardiac phenotype in humans [21].

References