Autoimmune diseases are the drawback of having a potent immune defence. Type 1 diabetes and myasthenia gravis are examples of such diseases, where disease development is both complex and multifactorial. In general, both genetic and environmental factors contribute, and among genes found to predispose, several are known to be shared between different autoimmune diseases. Examples of such genes are CTLA4 and PTPN22. This candidate gene study aims at delineating whether the cathepsin L2 (CTSL2) gene carry genetic variants predisposing to autoimmune diseases. CTSL2 is highly expressed in cortical thymic epithelial cells and has been shown to be up regulated in patients with myasthenia gravis. CTSL2 is an analogue to the murine cathepsin L gene, which previously has been suggested to play a role in development of diabetes in non-obese diabetic mice.
Four single nucleotide polymorphisms (SNP) and two microsatellites covering CTSL2 were genotyped in 429 Norwegian type 1 diabetes trio families, in addition to 83 German myasthenia gravis patients and 244 German controls. A haplotype consisting of two SNPs (rs10739289 and rs7875800) and one microsatellite (D9S971) was found to be associated with type 1 diabetes (34 transmitted vs. 13 non-transmitted, p=0.002). Another SNP, rs4743056, together with the D9S971 microsatellite, showed association with myasthenia gravis (14.3% in cases vs. 7.5% in controls, p=0.02), and an even stronger association with the early onset subgroup of myasthenia gravis (25% in cases vs. 7.5% in controls, p=0.007). Given the limited polymorphisms studied, and the associations found with different markers in the two diseases, the primary association has probably yet to be identified.
Functional analysis of CTSL2 was also performed. Expression of CTSL2 in fetal thymic tissue was observed, in addition to confirming expression in adult thymic tissue. The gene was extensively tested for alternative splice variants and several different mRNA transcripts of CTSL2 were identified. Furthermore, gene expression of CTSL2 was measured in 42 thymic tissue samples. We investigated whether the associated genotypes could reflect the earlier observed changes in gene expression, however no correlation was observed.
Our data suggest that CTSL2 could be a susceptibility gene for development of type 1 diabetes and myasthenia gravis, as well as an interesting candidate gene for other autoimmune diseases.