A novel mutation in the DNASE1 gene is related with protein instability and decreased enzyme activity in thyroid autoimmunity

A deficiency in the DNase enzyme, and thereby, a failure to remove DNA from nuclear antigens promotes disease susceptibility to autoimmune disorders. This study examined in patients with autoimmune thyroid disease (AITD) whether a reduced DNase activity is associated with sequence variations in the DNASE1 gene. The study included 18 patients with AITD, their 10 relatives, and 111 unrelated healthy controls. Serum DNase activity was determined with a validated, standardized enzyme-linked-immunosorbent assay. The promoter and all nine exons of the DNASE1 gene were sequenced. Heat stability of DNase enzyme was tested. In patients with AITD, a novel mutation (1218G > A, exon 5) and multiple polymorphisms were identified in the DNASE1 gene. The allele frequency of the mutation was increased in patients vs controls (P = 0.001). In contrast to controls, the novel mutation was present in all five members of a family with AITD showing decreased DNase activity. The mutation resulted in the replacement of highly conserved valine with methionine at amino acid position 89 of the DNase enzyme. It was related to lowered heat stability and lowered activity of the enzyme. The identified new mutation and numerous polymorphisms, noted for the first time in AITD patients, may alter transcription and translation of the DNASE1 gene, thereby decreasing the stability and activity of the corresponding enzyme.