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Query: UMLS:C0086543 (cataract)
 29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gap junctional intercellular communication (GJIC) is considered to play a key role in the maintenance of tissue independence and homeostasis in multicellular organisms by controlling the growth of GJIC-connected cells. Gap junction channels are composed of connexin molecules and, so far, more than a dozen different connexin genes have been shown to be expressed in mammals. Reflecting the importance of GJIC in various physiological functions, deletion of different connexin genes from mice results in various disorders, including cancers, heart malformation or conduction abnormality, cataract, etc. The possible involvement of aberrant GJIC in abnormal cell growth and carcinogenesis has long been postulated and recent studies in our own and other laboratories have confirmed that expression and function of connexin genes play an important role in cell growth control. Thus, almost all malignant cells show altered homologous and/or heterologous GJIC and are often associated with aberrant expression or localization of connexins. Aberrant localization of connexins in some tumour cells is associated with lack of function of cell adhesion molecules, suggesting the importance of cell-cell recognition for GJIC. Transfection of connexin genes into tumorigenic cells restores normal cell growth, supporting the idea that connexins form a family of tumour-suppressor genes. Some studies also show that specific connexins may be necessary to control growth of specific cell types. We have produced various dominant-negative mutants of Cx26, Cx32 and Cx43 and showed that some of them prevent the growth control exerted by the corresponding wild-type genes. However, we have found that connexins 32, 37 and 43 genes are rarely mutated in tumours. In some of these studies, we noted that connexin expression per se, rather than GJIC level, is more closely related to growth control, suggesting that connexins may have a GJIC-independent function. We have recently created a transgenic mouse strain in which a mutant Cx32 is specifically overexpressed in the liver. Studies with such mice indicate that Cx32 plays a key role in liver regeneration after partial hepatectomy. A decade ago, we proposed a method to enhance killing of cancer cells by diffusion of therapeutic agents through GJIC. Recently, we and others have shown that GJIC is responsible for the bystander effect seen in HSV-tk/ganciclovir gene therapy. Thus, connexin genes can exert dual effects in tumour control: tumour suppression and a bystander effect for cancer therapy.
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PMID:Role of connexin (gap junction) genes in cell growth control and carcinogenesis. 1019 67

Rapid advances in understanding the molecular biology of the gap junctional proteins - connexins (Cx) - have revealed that these proteins are indispensable for various cellular functions. Recent findings that mutational alterations of Cx genes leads to several quite different human diseases provide additional evidence that these proteins possess several not yet fully understood functions. Many different mutations of Cx32 have been found in the hereditary peripheral neuropathy - X-linked Charcot-Marie-Tooth syndrome and several mutations of Cx26 and Cx31 have been detected in deafness. Individual mutations of Cx46, Cx50 and Cx43 have been found in cataract or heart malformations. In this review, we analyzed the functional importance of mutations of different Cx described in different human diseases. Topological comparison of mutations in different Cx species has revealed several hot spots, where mutations are common for two different Cx or diseases. The value of Cx mutations associated with diseases for understanding Cx functions is discussed.
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PMID:Connexin gene mutations in human genetic diseases. 1076 31

In animal tissues, most cells are connected via intercellular cytoplasmic channels called gap junctions. Various electron microscopy techniques have made a crucial contribution to our understanding of the function and structure of gap junction channels. Tracer studies and freeze-fracture replica observations indicate that the connexon, the unit gap junction channel, is a pair of hemichannels apposed in the narrow intercellular gap between neighboring cell membranes. Recent advances in cellular biology have shown that connexon hemichannels are composed of hexamers of connexin proteins. Purification of the gap junction membrane and cDNA cloning analysis indicate the diversity of the connexin protein family, which contains more than 18 members, and their tissue- and cell type-specific distributions. Defects in some connexin genes may cause various hereditary diseases, such as X-linked Charcot-Marie-Tooth disease (Cx32), nonsyndromic autosomal deafness (Cx26), and cataract (Cx50). Analysis of gene knockout mice indicates that certain types of connexin play important roles in differentiation and development at crucial times in specific tissues and cell types.
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PMID:Diversity and molecular anatomy of gap junctions. 1179 89

Background: Congenital cataract is a significant cause of visual impairment and blindness. The present study examined the disease-causing mutations in three Chinese families with autosomal dominant congenital cataract (ADCC) to provide the preliminary evidence of the mechanisms underlying congenital cataract formation.Methods: Three pedigrees affected with ADCC were recruited. All participants underwent detailed ophthalmic examinations. Leucocyte DNA was extracted from venous blood for direct sequencing of candidate genes. In silico bioinformatics analysis was conducted to verify the functional impacts of the mutant proteins. Distribution patterns of connexin proteins were assessed through fluorescence microscopy using an enhanced green fluorescent protein (EGFP)-labeled expression vector in stably transfected Hek293 cells.Results: We identified three Chinese pedigrees with ADCC. Family 1 and family 2 presented with pulverized cataract and family 3 with an unknown phenotype. Direct sequencing of family 1 and family 2 revealed a missense mutation of c.64G>A encoding for G22S of connexin46 (Cx46), while a similar c.64G>A encoding for G22S of connexin50 (Cx50) was found in family 3; both mutations co-segregated well within all affected individuals in their families and were absent from 100 unrelated controls. Bioinformatics analysis revealed with high confidence that both mutations were deleterious. Confocal microscopy revealed the accumulation of both mutant connexins in the cytoplasm with punctate staining and a failure of gap junction formation between adjacent cells.Conclusions: Two novel G22S mutations of Cx46 and Cx50 were identified, and preliminary functional analysis revealed a potential deleterious effect of these mutations due to the malfunction of connexins.Abbreviations: ADCC: autosomal dominant congenital cataract; Cx26: connexin26; Cx32: connexin32; Cx46: connexin46; Cx46WT: wild-type connexin46; Cx50: Connexin50; Cx50WT: wild-type connexin50; DAPI: 4',6-diamidino-2-phenylindole; EGFP: enhanced green fluorescent protein; FBS: fetal bovine serum; GJA-:gap junction alpha-; PCR: polymerase chain reaction; PolyPhen: polymorphism phenotyping; PSIC: position-specific independent count; RPMI: Roswell Park Memorial Institute; TM1: first transmembrane.
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PMID:Identification and preliminary functional analysis of two novel congenital cataract associated mutations of Cx46 and Cx50. 3161 82