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Special Lectures

開催日 2014/9/13
時間 16:00 - 17:00
会場 Room A(Main Hall)
Chairperson(s) 水澤 英洋 / Hidehirohh Mizusawa (独立行政法人 国立精神・神経医療研究センター病院 / National Center Hospital, National Center of Neurology and Psychiatry)

Exploring molecular bases of neurological diseases

  • SL-3
  • 辻 省次 / Shoji Tsuji:1 
  • 1:東京大学医学部附属病院 神経内科・ゲノム医学センター / Medical Genome Center, Department of Neurology, The University of Tokyo Hospital 

During the past three decades, we have witnessed remarkable advances in understanding the molecular bases of hereditary neurological diseases by "positional cloning" strategies. The molecular bases of sporadic neurological diseases, however, largely remain unknown. Based on the "common disease-common variants hypothesis", genome-wide association studies (GWAS) have been extensively conducted to identify disease-susceptible genes. Although GWAS have successfully revealed numerous susceptibility genes for neurological diseases, odds ratios associated with these risk alleles are generally low and account for only a small portion of estimated heritability. Recent studies have revealed that the alleles with substantially large effect sizes are, in general, rare alleles, supporting the "common disease-multiple rare variants hypothesis". Since the power of detection of rare alleles by GWAS employing common SNPs is limited, comprehensive genome sequencing is required to identify these rare variants. The availability of next-generation sequencing technologies has made it possible to explore molecular bases of sporadic diseases.
Multiple system atrophy (MSA) is a progressive neurodegenerative disease with 12,000 patients in Japan, which is clinically characterized by autonomic failure in addition to various combinations of parkinsonism, and cerebellar ataxia. The molecular basis of MSA, however, remains unknown. Although MSA has been defined as a non-genetic disorder until recently, several multiplex MSA families have been reported, indicating that strong genetic factors confer susceptibility to the disease in multiplex families. Linkage analyses of 6 multiplex MSA families revealed several loci showing positive heterogeneity lod (HLOD) scores. Whole-genome sequencing of an individual with autopsy-proven MSA revealed a homozygous mutation (M78V-V343A) in COQ2. Co-segregating nonsynonymous mutations were confirmed in two of the six families. Based on large-scale case-control studies, we demonstrated that a common variant and multiple rare variants of COQ2, both of which are functionally impaired, are associated with an increased risk of sporadic MSA. COQ2 codes for an enzyme involved in the biosynthesis of CoQ10. A markedly decreased level of CoQ10 was indeed demonstrated in the cerebellum of a patient with the homozygous mutation. Supplementation with CoQ10 may be helpful in treating MSA, particularly for those with susceptibility-conferring COQ2 variants.

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