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Type X collagen: Analysis of mutations and transcriptional control
Başlık:
Type X collagen: Analysis of mutations and transcriptional control
Yazar:
Sweetman, Wendy Ann, author.
ISBN:
9780438043824
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (163 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-08C.
Özet:
Collagens are important structural components of the extracellular matrices of a variety of connective tissues and mutations in the genes encoding the constituent alpha-chains of collagen molecules are increasingly being recognised as a major cause of connective tissue disorders. Chondrodysplasias arise from disorders of the growth plate cartilage, a specialised connective tissue that is responsible for skeletal growth and development. Type X collagen is unique to this connective tissue and thus mutations within the gene encoding this molecule, the COL10A1 gene, may be responsible for causing certain forms of chondrodysplasia. A screening programme, was developed to look for mutations in the coding regions of the COL10A1 gene from individuals affected with a variety of chondrodysplasias. The screening programntutilised the polymerase chain reaction (PCR) and single stranded conformational polymorphism (SSCP) techniques, to analyse the COL10A1 coding region from genomic DNA samples. In all, seven sequence changes were identified within the regions of the gene analysed. Six of these changes were clearly demonstrated to be neutral sequence changes that were not responsible for causing any of the forms of chondrodysplasia studied. Some of these neutral sequence variants were used in segregational studies that demonstrated that the COL10A1 gene was not responsible for causing either of the disorders of achondroplasia or pseudoachondroplasia. The seventh sequence change was identified in two individuals with hypochondroplasia from a single pedigree. However, it was not possible to complete the segregation studies in this family and so the relevance of this sequence change to the disorder in this family remains uncertain. Type X collagen is known to be synthesized exclusively by hypertrophic chondrocytes and only at the time of endochondral ossification i.e. it is subject to cell specific and developmental controls. The mechanisms by which the transcription of the COL10A1 gene is so precisely regulated, however, remain unknown. The chick type X collagen gene has recently been reported to be under the control of multiple negative regulator elements or silencers (Lu Valle et alJ. Cell Biol. 121:1173-1179 1993). The absence of these elements allowed ectopic expression from a minimal promoter region when transformed into chick fibroblasts. The human COL10A1 promoter region was investigated for the presence of similar silencer elements. Attempts were first made to identify the untranslated exon 1 sequence of the human COL10A1 gene, and thereby locate the promoter region, using total RNA isolated from an osteoarthritic femoral head tissue sample and an anchored PCR technique. Constructs of the COL10A1 promoter region (containing between 25bp and 2.4 kb of sequence 5' of the TATA box) fused to the bacterial chloramphenicol acetyl transferase (CAT) reporter gene were obtained and transformed into a human fibroblast cell line (NHSl) alongside appropriate controls. No transcription from any of the human promoter constructs was observed, arguing against the presence of similar silencer elements as found in the chick promoter. The reasons for such an apparent divergence in the control mechanisms of the type X collagen gene between species remain unclear.
Notlar:
School code: 1543
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(684319.1) | 684319-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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