期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 91, 期 2, 页码 320-329出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2012.07.014
关键词
-
资金
- Global Centers of Excellence Program
- Integrated Database Project
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [B21406026, 23659458]
- Ministry of Health, Labour, and Welfare, Japan
- Research Committee of CNS Degenerative Diseases
- Ministry of Health, Labour, and Welfare of Japan
- Charcot-Marie-Tooth Association
- National Medical Research Council of Australia
- Japan Society for the Promotion of Science for Young Scientists
- [22129002]
- Grants-in-Aid for Scientific Research [23500428, 22129002, 24390220, 23659458, 24790348, 22129001] Funding Source: KAKEN
Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal-dominant neurodegenerative disorder characterized by widespread fasciculations, proximal-predominant muscle weakness, and atrophy followed by distal sensory involvement. To date, large families affected by HMSN-P have been reported from two different regions in Japan. Linkage and haplotype analyses of two previously reported families and two new families with the use of high-density SNP arrays further defined the minimum candidate region of 3.3 Mb in chromosomal region 3q12. Exome sequencing showed an identical c.854C>T (p.Pro285-Leu) mutation in the TRK-fused gene (TFG) in the four families. Detailed haplotype analysis suggested two independent origins of the mutation. Pathological studies of an autopsied patient revealed TFG- and ubiquitin-immunopositive cytoplasmic inclusions in the spinal and cortical motor neurons. Fragmentation of the Golgi apparatus, a frequent finding in amyotrophic lateral sclerosis, was also observed in the motor neurons with inclusion bodies. Moreover, TAR DNA-binding protein 43 kDa (TDP-43)-positive cytoplasmic inclusions were also demonstrated. In cultured cells expressing mutant TFG, cytoplasmic aggregation of TDP-43 was demonstrated. These findings indicate that formation of TFG-containing cytoplasmic inclusions and concomitant mislocalization of TDP-43 underlie motor neuron degeneration in HMSN-P. Pathological overlap of proteinopathies involving TFG and TDP-43 highlights a new pathway leading to motor neuron degeneration.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据