Disease relevance of CXADR

• 2. CXADR is a receptor for coxsackievirus and adenovirus [1].
• We show here that the receptor for coxsackie B viruses and adenoviruses 2 and 5 (CXADR) is expressed in mouse germ cells, suggesting the possibility that these viruses could infect germ cells [2].
• The gene for CAR, CXADR, is located within the genomic locus for Usher syndrome type 1E (USH1E) [3].
• The human cellular receptor for group B coxsackieviruses and adenoviruses (HCAR) is a transmembrane glycoprotein which belongs to the immunoglobulin superfamily [4].
• The distribution of hCAR in native tissue and the enhanced susceptibility of undifferentiated oropharyngeal epithelial cells, including undifferentiated cancer cells, to AdV infection has important implications for the development of AdV-based targeting strategies for the treatment of head and neck cancer or premalignancies [5].

High impact information on CXADR

• In addition, HCAR and MCAR mRNAs could be detected on Northern blots of oligo(dT)-selected RNA from receptor-positive HeLa cells and TCMK-1 as well as several tissues of human and mouse origin that are known to be targets for Ad and CVB infections [6].
• The leucine-rich peptide dictates the nuclear translocation of hCAR in response to various PB-type inducers and appears to be conserved in the mouse and rat receptors [7].
• Systemic administration of Ad in hCAR mice resulted in an increase in transgene expression in the lungs compared to wild-type mice, as determined using a luciferase reporter gene [8].
• A physical barrier, rather than hCAR status, may be the main determinant of transduction of intact epithelium [9].
• Expression of the hCAR adenovirus receptor, however, occurred throughout the full thickness of urothelium [9].

Biological context of CXADR

• A screen of two populations consisting of non-syndromic deaf and Usher 1 patients for mutations in CXADR revealed one haploid mutation (P356S) [3].
• We describe alternative splicing of the HCAR-gene and the existence of three exon-skipping splice variants in addition to the originally identified seven exon-encompassing mRNA transcript [4].
• Efficient adenoviral (AdV) infection largely depends on cellular expression of the human coxsackie and adenovirus receptor (hCAR); however, the relatively recent identification of this receptor precludes a comprehensive description of its tissue distribution [5].
• Since the mouse myoblasts, C2C12 cells, showed low sensitivity to infection by recombinant adenovirus 5, we initially infected these cells at a high multiplicity of infection (MOI) of 250 with the recombinant adenovirus containing hCAR cDNA and LacZ gene [10].
• Whereas HCAR expression in HeLa cells was constant with respect to cell density, HCAR expression in HUVEC increased with culture confluence [11].

Anatomical context of CXADR

• CONCLUSIONS: Low hCAR abundance may render normal human myocardium resistant to CAR-dependent viruses, whereas re-expression of hCAR, such as that observed in DCM, may be a key determinant of cardiac susceptibility to viral infections [12].
• Thus, elevated hCAR expression in mouse muscle fibers made a second virus inoculation at low doses possible [10].
• Primary cultures of human umbilical vein endothelial cells (HUVEC) express the human coxsackievirus and adenovirus receptor (HCAR) [11].
• To improve adenovirus-mediated gene delivery to skeletal muscle, we have used a recombinant adenovirus vector encoding the human Coxsackievirus and adenovirus receptor (hCAR) [10].
• In transfected polarized Madin-Darby canine kidney cells, wild-type hCAR was expressed selectively at the basolateral membrane, whereas hCAR lacking the transmembrane and/or cytoplasmic domains was expressed on both the basolateral and apical membranes [13].

Other interactions of CXADR

• We found that an adenoviral vector encoding human CD40L (AdhCD40L) was ineffective at transducing B-NHL cells because these cells lack the coxsackievirus B-adenovirus receptor and alpha(v) integrins [14].
• Analysis of the coxsackievirus B-adenovirus receptor gene in patients with myocarditis or dilated cardiomyopathy [15].

Analytical, diagnostic and therapeutic context of CXADR

• Finally, Western blots using antibodies that inhibit virus binding to either the human or mouse CVB receptors detected 46-kDa proteins in HCAR- and MCAR-transfected cells, respectively [6].
• The human coxsackievirus and adenovirus receptor (hCAR) was detected by immunofluorescence selectively at the basolateral surfaces of freshly excised human airway epithelial cells, suggesting that the absence of apical hCAR constitutes a barrier to adenovirus-mediated gene delivery in vivo [13].
• When the hCAR expression in 11 xenografts derived from Grade IV gliomas were compared to the levels detected in the original parental tumors, a mean 12-fold higher expression was seen in the xenografts (P = 0.01) [16].
• Our data also establishes the utility of transcriptionally targeted, Ad-mediated transient expression of human target molecules in the pulmonary vasculature of hCAR mice as models for in vivo analysis of targeted gene therapy vectors [17].
• With real-time PCR, we also analyzed hCAR expression in primary human astrocytomas of different malignancy grades, as well as in their xenograft derivatives [16].

References