論文

査読有り 国際誌
2018年7月

Phenotype variability and allelic heterogeneity in KMT2B-Associated disease.

Parkinsonism & related disorders
  • Toshitaka Kawarai
  • ,
  • Ryosuke Miyamoto
  • ,
  • Eiji Nakagawa
  • ,
  • Reiko Koichihara
  • ,
  • Takashi Sakamoto
  • ,
  • Hideo Mure
  • ,
  • Ryoma Morigaki
  • ,
  • Hidetaka Koizumi
  • ,
  • Ryosuke Oki
  • ,
  • Celeste Montecchiani
  • ,
  • Carlo Caltagirone
  • ,
  • Antonio Orlacchio
  • ,
  • Ayako Hattori
  • ,
  • Hideaki Mashimo
  • ,
  • Yuishin Izumi
  • ,
  • Takahiro Mezaki
  • ,
  • Satoko Kumada
  • ,
  • Makoto Taniguchi
  • ,
  • Fusako Yokochi
  • ,
  • Shinji Saitoh
  • ,
  • Satoshi Goto
  • ,
  • Ryuji Kaji

52
開始ページ
55
終了ページ
61
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.parkreldis.2018.03.022

BACKGROUND: Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with complex early-onset dystonia. Almost all reported KMT2B mutations occurred de novo in the paternal germline or in the early development of the patient. We describe clinico-genetic features on four Japanese patients with novel de novo mutations and demonstrate the phenotypic spectrum of KMT2B mutations. METHODS: We performed genetic studies, including trio-based whole exome sequencing (WES), in a cohort of Japanese patients with a seemingly sporadic early-onset generalized combined dystonia. Potential effects by the identified nucleotide variations were evaluated biologically. Genotype-phenotype correlations were also investigated. RESULTS: Four patients had de novo heterozygous mutations in KMT2B, c.309delG, c.1656dupC, c.3325_3326insC, and c.5636delG. Biological analysis of KMT2B mRNA levels showed a reduced expression of mutant transcript frame. All patients presented with motor milestone delay, microcephaly, mild psychomotor impairment, childhood-onset generalized dystonia and superimposed choreoathetosis or myoclonus. One patient cannot stand due to axial hypotonia associated with cerebellar dysfunction. Three patients had bilateral globus pallidal deep brain stimulation (DBS) with excellent or partial response. CONCLUSIONS: We further demonstrate the allelic heterogeneity and phenotypic variations of KMT2B-associated disease. Haploinsufficiency is one of molecular pathomechanisms underlying the disease. Cardinal clinical features include combined dystonia accompanying mild psychomotor disability. Cerebellum would be affected in KMT2B-associated disease.

リンク情報
DOI
https://doi.org/10.1016/j.parkreldis.2018.03.022
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/29653907

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