Endocrine Abstracts (2002) 3 P155

A nonsense mutation in exon two of the DNASE1 gene is not present in UK subjects with SLE and autoimmune thyroid disease

MJ Simmonds, JM Heward, A Allahabadia, H Foxall, C Gordon, JA Franklyn & SCL Gough


University of Birmingham, Department of Medicine, Clinical Research Block, Queen Elizabeth Hospital, Birmingham, UK.


Systemic lupus erythematosus (SLE) is characterised by the activation of autoreactive T and B cells and the production of autoantibodies. Concordance rates in monozygotic and dizygotic twins, along with familial clustering, suggest that SLE has a strong genetic component. Moreover, the co-existence of SLE and other autoimmune diseases within individuals, including autoimmune thyroid disease (ATD), suggests a sharing of general autoimmune susceptibility loci. Case control studies have shown that certain MHC class II and class III genes contribute to the susceptibility to SLE, although non-MHC loci have yet to be identified. The deoxyribonuclease I gene (DNASE1) on chromosome 16p13.3 produces an enzyme that hydrolyzes DNA, forming deoxyribonucleotides and in animal studies prevents the expansion of lymphocytes responsive to nucleosomal antigens, whose antibody products contribute to SLE. A heterozygous nonsense mutation in exon 2 of DNASE1 has recently been reported in Japanese patients with SLE. This resulted in decreased DNASE1 activity and a high immunoglobulin G titer against nucleosomal antigens, indicating that this gene could play a role in the genetic susceptibility to the autoimmune disease process in SLE. We genotyped 182 patients with SLE (12 of whom had a family history of ATD), 291 patients with Graves' disease, (5 of whom had a family history of SLE) and 285 control subjects for the DNASE1 mutation by PCR-RFLP. All subjects taking part in the study were of UK Caucasian origin and gave informed, written consent. The study was approved by the local ethics committee. Results revealed that none of the subjects examined had the DNASE1 mutation. Direct sequencing confirmed the results obtained by PCR-RFLP. These results suggest that the mutation in exon 2 of the DNASE1 gene is not contributing to the genetic susceptibility to the development of SLE or ATD in the UK.

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