講演情報
[O25-3]ミオクローヌス-ジストニア症例群における機能欠失型変異の同定
○東 剣虹1, 堀澤 士朗2, 福田 光成3, 熊田 聡子3, 川俣 貴一2, 平 孝臣2, 赤川 浩之1 (1.東京女子医科大学 総合医科学研究所, 2.東京女子医科大学 脳神経外科, 3.東京都立神経病院 神経小児科)
【Background】SGCE myoclonus-dystonia is a monogenic form of dystonia with autosomal dominant mode of inheritance, co-occurring with myoclonic jerks.
【Methods and Results】We present 12 Japanese patients from 9 families with this disease. Targeted next-generation sequencing covering major causative genes for monogenic dystonias identified 9 distinct SGCE mutations from each of the families; 3 nonsence, 2 frameshift, 2 missense, 1 in-frame 15bp deletion, and 1 splice donor site mutations, of which 4 were previously unreported. One missense mutation (c.662G＞T, p.Gly221Val) was located at the 3’end of exon5 (NM_001099400), which was predicted to cause aberrant splicing according to in silico predictions. Minigene assays, performed together with the c.825+1G＞C mutation, demonstrated complete skipping of exon5 and 6, respectively, in their transcripts. The other missense (c.1345A＞G, p.Met449Val) and the 15bp deletion (c.168_182del, p.Phe58_Leu62del) mutations showed significant reduction on the cell membrane expression via HiBiT bioluminescence assay.
【Conclusion】We concluded that all the detected mutations were disease-causing. Unlike the other detected mutations, p.Met449Val affects only the isoform 3 (NP_001092870 encoded by NM_001099400) among various known isoforms of SGCE. This isoform is brain-specific and mostly expressed in the cerebellum, which supports recent studies showing cerebellar dysfunction is the key element in the pathophysiology of SGCE myoclonus-dystonia.
【Methods and Results】We present 12 Japanese patients from 9 families with this disease. Targeted next-generation sequencing covering major causative genes for monogenic dystonias identified 9 distinct SGCE mutations from each of the families; 3 nonsence, 2 frameshift, 2 missense, 1 in-frame 15bp deletion, and 1 splice donor site mutations, of which 4 were previously unreported. One missense mutation (c.662G＞T, p.Gly221Val) was located at the 3’end of exon5 (NM_001099400), which was predicted to cause aberrant splicing according to in silico predictions. Minigene assays, performed together with the c.825+1G＞C mutation, demonstrated complete skipping of exon5 and 6, respectively, in their transcripts. The other missense (c.1345A＞G, p.Met449Val) and the 15bp deletion (c.168_182del, p.Phe58_Leu62del) mutations showed significant reduction on the cell membrane expression via HiBiT bioluminescence assay.
【Conclusion】We concluded that all the detected mutations were disease-causing. Unlike the other detected mutations, p.Met449Val affects only the isoform 3 (NP_001092870 encoded by NM_001099400) among various known isoforms of SGCE. This isoform is brain-specific and mostly expressed in the cerebellum, which supports recent studies showing cerebellar dysfunction is the key element in the pathophysiology of SGCE myoclonus-dystonia.