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Parkinson's Disease and Related Disorders

開催日 2014/9/11
時間 16:00 - 17:00
会場 Poster / Exhibition(Event Hall B)

A novel insertion mutation of MAPT causes FTDP-17

  • P1-308
  • 森野 豊之 / Hiroyuki Morino:1 松田 由喜子 / Yukiko Matsuda:1 平木 啓子 / Keiko Hiraki:1 倉重 毅志 / Takashi Kurashige:2 和泉 唯信 / Yuishin Izumi:3 山崎 雄 / Yuu Yamasaki:2 高橋 哲也 / Tetsuya Takahashi:2 丸山 博文 / Hirofumi Maruyama:2 伊東 秀文 / Hidefumi Ito:4 川上 秀史 / Hideshi Kawakami:1 
  • 1:広島大学原爆放射線医科学研究所 分子疫学研究分野 / Dept of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima Univ 2:広島大学大学院医歯薬保健学研究院 脳神経内科学 / Dept of Clinical Neuroscience & Therapeutics, Institute of Biomedical & Health Sciences, Hiroshima Univ 3:徳島大学大学院 臨床神経化学分野 / Dept of Clinical Neuroscience, Graduate School of Med, Univ of Tokushima Graduate School 4:和歌山県立医科大学 神経内科学 / Dept of Neurology, Graduate School of Med, Wakayama Med Univ 

MAPT, LRRK2, GRN, and C9orf72 are known as responsible genes for several neurological disorders, including progressive supranuclear palsy (PSP), Parkinson's disease (PD), and frontotemporal dementia (FTD). We conducted genetic analysis of a family in which there were several patients with PSP, PD, and FTD over two generations in order to identify the causative gene.
We performed high-density SNP typing on 3 affected and 2 unaffected persons, followed by exome sequencing on 3 affected persons. Linkage analysis and Homozygosity Haplotyping based on the results of the high-density SNP analysis exhibited candidate region. Exome sequencing was performed, and the variants were obtained using BWA, Samtools, Picard, and GATK. We reduced the candidates by referring to the public variant databases, and confirmed the remained mutations by Sanger sequencing. In addition, we screened for the mutations on other patients.
Relatively long segments of high LOD score exist on chromosome 6, 9, 14, 17, and 20. Homozygosity Haplotyping indicated common haplotype regions only to the patients in chromosome 13 and 17. From the result of exome sequencing, 2 novel variants were remained finally, and one of the variants was located in microtubule-associated protein tau (MAPT) on chromosome 17. The same variant was observed in the 2 PD patients of another family, and the haplotype around the variant was coincident with that of the index family.
The novel MAPT variant we identified is considered to cause neurodegenerative diseases. The variant is located in the region in which several mutations were reported previously, but it is much characteristic that the variant is non-frameshift insertion adding an amino acid. In the further investigation, we hope to reveal the pathogenic mechanism by evaluating biochemical changes associated with the mutation.

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