👤 Pentti J Tienari

Somatic mutations have a central role in cancer but their role in other diseases such as autoimmune disorders is poorly understood. Earlier work has provided indirect evidence of rare somatic mutations in autoreactive T-lymphocytes in multiple sclerosis (MS) patients but such mutations have not been identified thus far. We analysed somatic mutations in blood in 16 patients with relapsing MS and 4 with other neurological autoimmune disease. To facilitate the detection of somatic mutations CD4+, CD8+, CD19+ and CD4-/CD8-/CD19- cell subpopulations were separated. We performed next-generation DNA sequencing targeting 986 immune-related genes. Somatic mutations were called by comparing the sequence data of each cell subpopulation to other subpopulations of the same patient and validated by amplicon sequencing. We found non-synonymous somatic mutations in 12 (60%) patients (10 MS, 1 myasthenia gravis, 1 narcolepsy). There were 27 mutations, all different and mostly novel (67%). They were discovered at subpopulation-wise allelic fractions of 0.2%-4.6% (median 0.95%). Multiple mutations were found in 8 patients. The mutations were enriched in CD8+ cells (85% of mutations). In follow-up after a median time of 2.3years, 96% of the mutations were still detectable. These results unravel a novel class of persistent somatic mutations, many of which were in genes that may play a role in autoimmunity (ATM, BTK, CD46, CD180, CLIP2, HMMR, IKFZF3, ITGB3, KIR3DL2, MAPK10, CD56/NCAM1, RBM6, RORA, RPA1 and STAT3). Whether some of this class of mutations plays a role in disease is currently unclear, but these results define an interesting hitherto unknown research target for future studies. Show less

A possible role of allelic variation on chromosome 19q13 in multiple sclerosis (MS) susceptibility has been suggested. We tested association of sixteen 19q13 markers with MS in 459 families. Nominally significant associations were tested in an independent set of 323 families as well as in the pooled set of 782 families. We were not able to confirm previously suggested associations with APOE, GIPR, ZNF45, ILT6 and D19S585. In the screening dataset nominally significant associations were found with D19S867 and with APOE haplotype (p=0.007 in both), but these were not replicated in the independent dataset nor in the pooled analysis of 757 families. Thus, we were not able to detect any statistically significant allelic associations. Re-sequencing based approaches may be required for elucidating the role chromosome 19q13 with MS. Show less