Artlett, Carolyn May; (1996) Molecular characterisation of chromosomal instability in scleroderma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Scleroderma is not considered to be a disorder of chromosomal instability, but previous cytogenetic analyses have reported a wide range of chromosomal abnormalities in these patients and family members. In this study, peripheral leukocytes from 49 scleroderma, 45 control families were examined for chromosomal abnormalities using Variable Number Tandem Repeats (VNTR) and telomere repeat probes. In addition to leukocytes, paired fibroblast cell lines from the involved and uninvolved skin of 27 patients were examined. VNTRs and telomere lengths have been used to monitor chromosomal instability in tumour cell lines and the elderly. Tumour cell lines and the elderly have been reported to have short telomeres and unstable VNTRs and a higher rate of chromosomal instability. The loss of large amounts of telomeric DNA is thought to be one of the causes of senescence in a cell. All families were typed for Class I Cw alleles and Class II -DRB, -DQA and -DQB to confirm family membership and families were also typed for Class III complement component C4 alleles. There were significant rises in the level of VNTR chromosomal anomalies in scleroderma patients (36.7[percent], n=18), their siblings (16.3[percent], n=13), and offspring (21.7[percent], n=15). Chromosomal mutations in the control group was 8.0[percent] (n=7). The most common VNTR site for mutation was pYNZ22 (17p13.4). Differences were also seen in the VNTR alleles between fibroblast and leukocyte DNA from the same patient. The average loss of telomeric DNA in SSc patients and family members was found to be 3Kb. This loss was not related to age or the duration of the disease. The results may reflect a genetic predisposition for chromosomal instability, or due to close living proximity and exposure to a common environmental agent. Molecular alterations of VNTRs telomeres were observed in scleroderma patients, relatives and offspring. The reason for the genomic changes remains unknown, but previous studies have implicated a clastogen. A wide variety of common environmental agents are known to produce chromosomal aberrations; these include viruses, pesticides, air pollutants and drugs. Scleroderma like syndromes may be induced by some of these agents.

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