Cleft Lip in Oculodentodigital Dysplasia Suggests Novel Roles for Connexin43

Amano, Katsuhiko; Ishiguchi, Mitsuko; Aikawa, Tomonao; Kimata, Masaaki; Kishi, Naoko; Fujimaki, Takamitsu; Murakami, Akiko; Kogo, Mikihiko

doi:10.1177/0022034512447952

Cited by 12 publications

(9 citation statements)

References 27 publications

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“…Abnormalities in primary and permanent teeth such as microdontia, partial anodontia, enamel hypoplasia, caries, and early tooth loss are observed in most patients. Brittle nails and hair abnormalities sometimes appear and skin diseases like palmoplantar keratoderma and subclinical wound healing defects are possible as well (Paznekas et al, 2003; Gong et al, 2006; Thibodeau et al, 2010; Churko et al, 2011; Amano et al, 2012). …”

Section: Introduction: Oddd Mutations Clinical Manifestations and Rementioning

confidence: 99%

Neurological manifestations of oculodentodigital dysplasia: a Cx43 channelopathy of the central nervous system?

et al. 2013

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The coordination of tissue function is mediated by gap junctions (GJs) that enable direct cell–cell transfer of metabolic and electric signals. GJs are formed by connexins of which Cx43 is most widespread in the human body. In the brain, Cx43 GJs are mostly found in astroglia where they coordinate the propagation of Ca2+ waves, spatial K+ buffering, and distribution of glucose. Beyond its role in direct intercellular communication, Cx43 also forms unapposed, non-junctional hemichannels in the plasma membrane of glial cells. These allow the passage of several neuro- and gliotransmitters that may, combined with downstream paracrine signaling, complement direct GJ communication among glial cells and sustain glial-neuronal signaling. Mutations in the GJA1 gene encoding Cx43 have been identified in a rare, mostly autosomal dominant syndrome called oculodentodigital dysplasia (ODDD). ODDD patients display a pleiotropic phenotype reflected by eye, hand, teeth, and foot abnormalities, as well as craniofacial and bone malformations. Remarkably, neurological symptoms such as dysarthria, neurogenic bladder (manifested as urinary incontinence), spasticity or muscle weakness, ataxia, and epilepsy are other prominent features observed in ODDD patients. Over 10 mutations detected in patients diagnosed with neurological disorders are associated with altered functionality of Cx43 GJs/hemichannels, but the link between ODDD-related abnormal channel activities and neurologic phenotype is still elusive. Here, we present an overview on the nature of the mutants conveying structural and functional changes of Cx43 channels and discuss available evidence for aberrant Cx43 GJ and hemichannel function. In a final step, we examine the possibilities of how channel dysfunction may lead to some of the neurological manifestations of ODDD.

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Section: Introduction: Oddd Mutations Clinical Manifestations and Rementioning

confidence: 99%

Neurological manifestations of oculodentodigital dysplasia: a Cx43 channelopathy of the central nervous system?

et al. 2013

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“…Gap junctions are essential for proper cell homeostasis and have been shown to play important roles in a wide variety of biological and pathological processes [24]. Mutations in CX43 gene cause oculodentodigital dysplasia, which is characterized among several clinical phenotypes by the presence of cleft lip and/or cleft palate [25,26]. …”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in FGF12, VCL, CX43 and VAX1in Brazilian patients with nonsyndromic cleft lip with or without cleft palate

et al. 2013

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BackgroundNonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common orofacial birth defect with a wide range prevalence among different populations. Previous association studies with populations from Europe and Asia have identified putative susceptibility markers for NSCL/P in fibroblast growth factor 12 (FGF12), vinculin (VCL), connexin 43 (CX43) and in a region close to the ventral anterior homeobox 1 (VAX1) gene. However, there have thus far been no studies of these markers in NSCL/P Brazilian patients, and as the genetic ancestry of the Brazilian population is highly varied, the predisposition to those disease markers can be different.MethodsHerein we conducted a structured association study conditioned on the individual ancestry proportions to determine the role of 16 polymorphic markers within those genes in 300 patients with NSCL/P and 385 unaffected controls.ResultsNone of the alleles and genotypes showed association with NSCL/P, though there was a significant association of the haplotype formed by VAX1 rs10787760, rs6585429 and rs1871345 polymorphisms with NSCL/P that did not persist Bonferroni correction for multiple tests.ConclusionsOur results are consistent with a lack of involvement of FGF12, VCL and CX43 variants with NSCL/P pathogenesis in Brazilian patients. Furthermore, the higher frequency of a haplotype of VAX1 with NSCL/P patients suggests a low penetrant gene for oral cleft, and warrants further studies.

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“…This appears important as the prevalence of osteocyte apoptosis is augmented in conditions associated with increased risk of bone fractures such as glucocorticoidinduced osteoporosis and sex steroid defi ciency, which is both successfully treated with BPs (Plotkin et al, 2002;Weinstein, 2000;Weinstein et al, 1998). Cx43 appears to be responsible for synchronized cell actions at tissue level, as observed to be indispensable in bone development, remodeling, and recovery (Izu et al, 2011;Watkins et al, 2012;Chaible et al, 2011;Amano et al, 2012). In this context, Cx43-derived hemichannels and GJIC appears to be necessary for basal survival signaling mediated by Src and Erk kinase as well as for signal transduction in physiological stimuli and noxae and for the regulation of osteoclastic differentiation and function (Plotkin & Bellido, 2001;Plotkin et al, 2002;Kylm ä oja et al, 2013).…”

Section: Connexin Hemichannels and Gap Junctions In Bone Strengthmentioning

confidence: 99%

Bisphosphonates and Connexin 43: A Critical Review of Evidence

Sadr-Eshkevari

Ashnagar

Rashad

et al. 2014

Cell Communication & Adhesion

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Bisphosphonates (BPs) are drugs commonly used in the treatment of various disease arising or affecting bone tissue. There is a standard use in bone neoplasia and metastasis, hormonal and developmental disorders as well as for compensation of adverse effects in several medical therapies. Many in-vivo and in-vitro studies have assessed the effi cacy of this drug and its function in cellular scale. In this concern, BPs are described to inhibit the resorptive function of osteoclasts and to prevent apoptosis of osteoblasts and osteocytes. They can preserve the osteocytic network, reduce fracture rate, and increase the bone mineral content, which is therapeutically used. Connexin 43 (Cx43) is a crucial molecule for basal regulation of bone homeostasis, development, and differentiation. It is described for signal transduction in many physiological and pathological stimuli and recently to be involved in BP action.

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Cleft Lip in Oculodentodigital Dysplasia Suggests Novel Roles for Connexin43

Cited by 12 publications

References 27 publications

Neurological manifestations of oculodentodigital dysplasia: a Cx43 channelopathy of the central nervous system?

Neurological manifestations of oculodentodigital dysplasia: a Cx43 channelopathy of the central nervous system?

Polymorphisms in FGF12, VCL, CX43 and VAX1in Brazilian patients with nonsyndromic cleft lip with or without cleft palate

Bisphosphonates and Connexin 43: A Critical Review of Evidence

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