The TRK-Fused Gene Is Mutated in Hereditary Motor and Sensory Neuropathy with Proximal Dominant Involvement

• Published in: American journal of human genetics Vol. 91; no. 2; pp. 320 - 329
• Main Authors: Ishiura, Hiroyuki, Sako, Wataru, Yoshida, Mari, Kawarai, Toshitaka, Tanabe, Osamu, Goto, Jun, Takahashi, Yuji, Date, Hidetoshi, Mitsui, Jun, Ahsan, Budrul, Ichikawa, Yaeko, Iwata, Atsushi, Yoshino, Hiide, Izumi, Yuishin, Fujita, Koji, Maeda, Kouji, Goto, Satoshi, Koizumi, Hidetaka, Morigaki, Ryoma, Ikemura, Masako, Yamauchi, Naoko, Murayama, Shigeo, Nicholson, Garth A., Ito, Hidefumi, Sobue, Gen, Nakagawa, Masanori, Kaji, Ryuji, Tsuji, Shoji
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 10.08.2012; Cell Press; Elsevier
• Subjects: Base Sequence; Biological and medical sciences; Chromosomes; Chromosomes, Human, Pair 3 - genetics; DNA-Binding Proteins - genetics; Exome - genetics; Fundamental and applied biological sciences. Psychology; Gene expression; Genetic Linkage; Genetic Predisposition to Disease - genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Golgi Apparatus - pathology; Haplotypes - genetics; Hereditary Sensory and Motor Neuropathy - genetics; Hereditary Sensory and Motor Neuropathy - pathology; Humans; Inclusion Bodies - pathology; Japan; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Motor Neurons - pathology; Mutation; Neurological disorders; Pedigree; Point Mutation - genetics; Polymorphism, Single Nucleotide - genetics; Proteins; Proteins - genetics; Sequence Analysis, DNA; Japan; Proximal; Nervous system diseases; Gene; Genetics; Dominant character; Neuropathy; Hereditary; Genetic disease
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2012.07.014

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.