Haploinsufficiency of TNXB Is Associated with Hypermobility Type of Ehlers-Danlos Syndrome

Department of Pediatrics, University of California, San Francisco, San Francisco, California, United States
The American Journal of Human Genetics (Impact Factor: 10.93). 08/2003; 73(1):214-7. DOI: 10.1086/376564
Source: PubMed
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Available from: Marisol E Otero, Nov 26, 2014
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    • "Symptoms range from musculoskeletal pain to easy bruising and velvety skin (Beighton et al. 1998) in hypermobility type and muscle weakness, skin hyperextensibility, velvety skin, and easy bruising (Voermans et al. 2007) in tenascin-X deficiency type EDS. Although tenascin-X protein is abundantly expressed in almost all the connective tissues (Zweers et al. 2003), it is not expressed in lymphoid organs. Therefore, the apparently incongruous location of TNXB within the MHC class III region prompted us to hypothesize its association with morphostructural and physiological indices because any of the MHC class III genes could contain sequences that affect productivity either alone or in linkage disequilibrium with other disadvantageous alleles in other genes (Walsh et al. 2003). "
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    ABSTRACT: The tenascin-XB (TNXB) gene has antiadhesive effects, functions in matrix maturation in connective tissues, and localizes to the major histocompatibility complex class III region. We hypothesized that it may influence adaptive physiological response through an effect on blood vessel function. We identified a novel g.1324 A→G polymorphism at a TaqI recognition site in a 454 bp fragment of ovine TNXB and genotyped it in 150 Nigerian sheep using PCR-RFLP. The missense mutation changes glutamic acid (GAA) to glycine (GGA). Among SNP genotypes, significant differences (P < 0.05) were observed in body weight and fore cannon bone length. Interaction effects of breed, SNP genotype, and geographic location had a significant effect (P < 0.05) on chest girth. The SNP genotype was significantly (P < 0.05) associated with physiological traits of pulse rate and skin temperature. The observed effect of this novel polymorphism may be mediated through its role in connective tissue biology, requiring further association and functional studies.
    Full-text · Article · Jul 2013 · Biochemical Genetics
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    • "In the past, a handful of papers tried to clarify the conundrum. In particular, some molecular investigations suggested that TNXB heterozygous or homozygous mutations can be identified in ~5% of the EDS-HT patients [34, 35]. Subsequently, EDS patients harboring mutations in TNXB have been classified in a different EDS subtype (i.e., TNXB-deficient EDS) due to an apparently distinct phenotype [36]. "
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    ABSTRACT: Ehlers-Danlos syndrome, hypermobility type, constituting a phenotypic continuum with or, perhaps, corresponding to the joint hypermobility syndrome (JHS/EDS-HT), is likely the most common, though the least recognized, heritable connective tissue disorder. Known for decades as a hereditary condition with predominant rheumatologic manifestations, it is now emerging as a multisystemic disorder with widespread manifestations. Nevertheless, the practitioners' awareness of this condition is generally poor and most patients await years or, perhaps, decades before reaching the correct diagnosis. Among the various sites of disease manifestations, skin and mucosae represent a neglected organ where the dermatologist can easily spot diagnostic clues, which consistently integrate joint hypermobility and other orthopedic/neurologic manifestations at physical examination. In this paper, actual knowledge on JHS/EDS-HT is summarized in various sections. Particular attention has been posed on overlooked manifestations, including cutaneous, mucosal, and oropharyngeal features, and early diagnosis techniques, as a major point of interest for the practicing dermatologist. Actual research progresses on JH/EDS-HT envisage an unexpected link between heritable dysfunctions of the connective tissue and a wide range of functional somatic syndromes, most of them commonly diagnosed in the office of various specialists, comprising dermatologists.
    Full-text · Article · Nov 2012
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    • "Tenascin, an oligomeric extracellular matrix protein, was one of the first myotendinous junction markers (Chiquet and Fambrough, 1984). Notably, mutations in tenascin XB gene cause Ehlers–Danlos syndrome (Zweers et al., 2003), with muscle weakness and contractures and secondary deficiency of collagen VI, overlapping with the collagen VI myopathies phenotype (Voermans et al., 2007), and pointing to a possible functional interaction between these myotendinous junction components. Therefore α5 gene mutation screening might result appealing in those cases of Ehlers–Danlos disease which are negative for known mutations. "
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    ABSTRACT: Collagen VI is a major extracellular matrix (ECM) protein with a critical role in maintaining skeletal muscle functional integrity. Mutations in COL6A1, COL6A2 and COL6A3 genes cause Ullrich Congenital Muscular Dystrophy (UCMD), Bethlem Myopathy, and Myosclerosis. Moreover, Col6a1(-/-) mice and collagen VI deficient zebrafish display a myopathic phenotype. Recently, two additional collagen VI chains were identified in humans, the α5 and α6 chains, however their distribution patterns and functions in human skeletal muscle have not been thoroughly investigated yet. By means of immunofluorescence analysis, the α6 chain was detected in the endomysium and perimysium, while the α5 chain labeling was restricted to the myotendinous junctions. In normal muscle cultures, the α6 chain was present in traces in the ECM, while the α5 chain was not detected. In the absence of ascorbic acid, the α6 chain was mainly accumulated into the cytoplasm of a sub-set of desmin negative cells, likely of interstitial origin, which can be considered myofibroblasts as they expressed α-smooth muscle actin. TGF-β1 treatment, a pro-fibrotic factor which induces trans-differentiation of fibroblasts into myofibroblasts, increased the α6 chain deposition in the extracellular matrix after addition of ascorbic acid. In order to define the involvement of the α6 chain in muscle fibrosis we studied biopsies of patients affected by Duchenne Muscular Dystrophy (DMD). We found that the α6 chain was dramatically up-regulated in fibrotic areas where, in contrast, the α5 chain was undetectable. Our results show a restricted and differential distribution of the novel α6 and α5 chains in skeletal muscle when compared to the widely distributed, homologous α3 chain, suggesting that these new chains may play specific roles in specialized ECM structures. While the α5 chain may have a specialized function in tissue areas subjected to tensile stress, the α6 chain appears implicated in ECM remodeling during muscle fibrosis.
    Full-text · Article · Apr 2012 · Matrix biology: journal of the International Society for Matrix Biology
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