title: The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement.
abstract: 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.Pro285Leu) 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.
authors.affiliation: Department of Neurology, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishiura
authors.forename: Wataru
authors.initials: W
authors.lastname: Sako
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.forename: Osamu
authors.initials: O
authors.lastname: Tanabe
authors.forename: Jun
authors.initials: J
authors.lastname: Goto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Date
authors.forename: Jun
authors.initials: J
authors.lastname: Mitsui
authors.forename: Budrul
authors.initials: B
authors.lastname: Ahsan
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwata
authors.forename: Hiide
authors.initials: H
authors.lastname: Yoshino
authors.forename: Yuishin
authors.initials: Y
authors.lastname: Izumi
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.forename: Kouji
authors.initials: K
authors.lastname: Maeda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Goto
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Koizumi
authors.forename: Ryoma
authors.initials: R
authors.lastname: Morigaki
authors.forename: Masako
authors.initials: M
authors.lastname: Ikemura
authors.forename: Naoko
authors.initials: N
authors.lastname: Yamauchi
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
mesh_terms: D001483:Base Sequence; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome / Q000235:genetics; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006056:Golgi Apparatus / Q000473:pathology; D006239:Haplotypes / Q000235:genetics; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology; D007564:Japan; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000473:pathology; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D033921:Vesicular Transport Proteins
chemical_list: D004268:DNA-Binding Proteins; D011506:Proteins; C096163:TFG protein, human; D033921:Vesicular Transport Proteins