PP13.9 – 2836: Variants in the NR3C2 gene as possible genetic predisposition for the development of multiple sclerosis

Abstract

Objective Due to the incidental finding of two NR3C2 gene variants in young MS patients, we investigated the possibility that NR3C2 might be a suspectibility gene for multiple sclerosis (MS) and autoimmune disease. Methods In two unrelated MS cases we found respectively a deletion and a point mutation within the coding region of the NR3C2 gene using array-comparative genomic hybridization (Agilent 180k) and Sanger sequencing of NR3C2. The latter was also performed in an independent cohort of 100 MS probands. Results Case 1 is a male 12 years-old MS patient. Array-comparative genomic hybridization revealed a 112–181 kb deletion in NR3C2, compatible with the diagnosis of type 1 pseudohypoaldosteronism. He had no symptoms of this disease but serial blood investigations confirmed a mild elevation of aldosterone. Segregation analysis revealed that his mother and maternal aunt, both of which developed autoimmune thyroiditis, carried the same microdeletion. Case 2 is the mother of a child with pseudohypoaldosteronism. She presented at age 28 with MS and was known to carry the same mutation (c.1757+1G>C) as her daughter in the splice donor site of intron 2 of NR3C2. The mother had elevated aldosterone levels. In an independent MS cohort, we detected a loss-of-function mutation (p.Ser585X) in a single patient with early-onset MS and a positive familial history. She had no symptoms of pseudohypoaldosteronism but a mild but reproducible elevation of aldosterone was detected. Conclusion Our data suggest that NR3C2 loss-of-function variants may associate with a genetic predisposition for developing autoimmune disease, particularly for MS. Though further validation of our findings in a larger cohort is necessary the possible involvement of the renin-angiotensin-aldosterone system in the pathogenesis of MS may have important implications in counselling and follow up of patients with NR3C2 mutations and opens novel perspectives for MS treatment.