Loss‐of‐function mutations in SGCE found in Japanese patients with myoclonus‐dystonia

Autor: Kenko, Azuma, Shiro, Horisawa, Hideaki, Mashimo, Mitsumasa, Fukuda, Satoko, Kumada, Takakazu, Kawamata, Takaomi, Taira, Hiroyuki, Akagawa
Rok vydání: 2022
Předmět:
Zdroj: Clinical Genetics. 103:209-213
ISSN: 1399-0004
0009-9163
0010-9940
DOI: 10.1111/cge.14233
Popis: SGCE myoclonus-dystonia is a monogenic form of dystonia with an autosomal dominant mode of inheritance that co-occurs with a myoclonic jerk. In this study, we present 12 Japanese patients from nine families with this disease. Targeted next-generation sequencing covering major causative genes for monogenic dystonias identified nine distinct SGCE mutations from each of the families: three nonsense, two frameshift, two missense, one in-frame 15 bp deletion, and one splice donor site mutations, of which four were previously unreported. One missense mutation (c.662GT, p.Gly221Val) was located at the 3' end of exon 5 (NM_001099400), which was predicted to cause aberrant splicing according to in silico predictions. Minigene assays performed together with the c.825+1GC mutation demonstrated complete skipping of exon 5 and 6, respectively, in their transcripts. The other missense (c.1345AG, p.Met449Val) and 15 bp deletion (c.168_182del, p.Phe58_Leu62del) mutations showed a significant reduction in cell membrane expression via HiBiT bioluminescence assay. Therefore, we concluded that all the detected mutations were disease-causing. Unlike the other detected mutations, p.Met449Val affects only isoform 3 (NP_001092870 encoded by NM_001099400) among the variously known isoforms of SGCE. This isoform is brain-specific and is mostly expressed in the cerebellum, which supports recent studies showing that cerebellar dysfunction is a key element in the pathophysiology of SGCE myoclonus-dystonia.
Databáze: OpenAIRE
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