TDP-43 M337V mutation in familial amyotrophic lateral sclerosis in Japan.
The clinical features of a Japanese family with autosomal dominant adult-onset amyotrophic lateral sclerosis (ALS) are reported. Weakness initially affected the bulbar musculature, with later involvement of the extremities. Genetic studies failed to detect any mutations of the Cu/Zn superoxide dismutase-1 (SOD1) and Dynactin1 (DCTN1) genes, but revealed a single base pair change from wild-type adenine to guanine at position 1009 in TAR-DNA-binding protein (TDP-43), resulting in a methionine-to-valine substitution at position 337. The immunohistochemical study on autopsied brain of the proband's aunt showed TDP-43-positive cytoplasmic inclusions in the anterior horn cells of the spinal cord and in the hypoglossal nucleus, as well as glial cytoplasmic inclusions in the precentral gyrus, suggesting that a neuroglial proteinopathy was related to TDP-43. In conclusion, a characteristic clinical phenotype of familial ALS with initial bulbar symptoms occurred in this family with TDP-43 M337V substitution, the pathomechanism of which should be elucidated.
Department of Neurology, Doctoral Program in Medical Sciences for Control of Pathological Processes, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba. atamaoka@md.tsukuba.ac.jp
Akira
A
Tamaoka
Makoto
M
Arai
Masanari
M
Itokawa
Tetsuaki
T
Arai
Masato
M
Hasegawa
Kuniaki
K
Tsuchiya
Hiroshi
H
Takuma
Hiroshi
H
Tsuji
Akiko
A
Ishii
Masahiko
M
Watanabe
Yuji
Y
Takahashi
Jun
J
Goto
Shoji
S
Tsuji
Haruhiko
H
Akiyama
D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D000072159:Dynactin Complex; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D007564:Japan; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
C000606360:DCTN1 protein, human; D004268:DNA-Binding Proteins; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1