Identification of novel TFG mutation in HMSN-P pedigree: Emphasis on variable clinical presentations

Khani, Marzieh; Shamshiri, Hosein; Alavi, Afagh; Nafissi, Shahriar; Elahi, Elahe

doi:10.1016/j.jns.2016.08.035

Cited by 11 publications

(11 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Clinically, a high incidence of glucose intolerance (7 with non-insulin-dependent diabetes mellitus (NIDDM) and 4 with impaired glucose tolerance (IGT) among 16 patients) was reported in patients with HMSN-P 13 , and two heterozygous missense mutations of TFG have been identified to date as being causative 6–8 . Given that the heterozygous TFG mutation is sufficient to cause HMSN-P and that TFG-positive cytoplasmic inclusions were observed in the motor neurons of one patient 6 , glucose intolerance in HMSN-P patients might be attributable to the cytotoxicity of abnormal TFG rather than to lack of TFG function as shown in our study.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, TFG was recently identified as a causative gene for several neurodegenerative diseases, such as hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) 6–8 , the axonal type of Charcot-Marie-Tooth disease 9 and hereditary spastic paraplegia (HSP) 10–12 . Among HMSN-P patients, high incidences of diabetes mellitus and dyslipidemia have been reported 13 , yet nothing is known about the role of TFG in the regulation of glucose or lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Yamamotoya

Nakatsu

Kushiyama

et al. 2017

Sci Rep

View full text Add to dashboard Cite

The Trk-fused gene (TFG) is reportedly involved in the process of COPII-mediated vesicle transport and missense mutations in TFG cause several neurodegenerative diseases including hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). The high coincidence ratio between HMSN-P and diabetes mellitus suggests TFG to have an important role(s) in glucose homeostasis. To examine this possibility, β-cell specific TFG knockout mice (βTFG KO) were generated. Interestingly, βTFG KO displayed marked glucose intolerance with reduced insulin secretion. Immunohistochemical analysis revealed smaller β-cell masses in βTFG KO than in controls, likely attributable to diminished β-cell proliferation. Consistently, β-cell expansion in response to a high-fat, high-sucrose (HFHS) diet was significantly impaired in βTFG KO. Furthermore, glucose-induced insulin secretion was also markedly impaired in islets isolated from βTFG KO. Electron microscopic observation revealed endoplasmic reticulum (ER) dilatation, suggestive of ER stress, and smaller insulin crystal diameters in β-cells of βTFG KO. Microarray gene expression analysis indicated downregulation of NF-E2 related factor 2 (Nrf2) and its downstream genes in TFG depleted islets. Collectively, TFG in pancreatic β-cells plays a vital role in maintaining both the mass and function of β-cells, and its dysfunction increases the tendency to develop glucose intolerance.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Yamamotoya

Nakatsu

Kushiyama

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Clinical descriptions in the more recently diagnosed patients from Iran emphasized variability in presentations. For example, presence of prominent effects on sensory nerves, comparable involvement of proximal and distal muscles, cranial nerve involvement, and rapid progression were observed in some patients (Alavi et al, ; Khani, Shamshiri, Alavi, Nafissi, & Elahi, ). Pattern of disease inheritance in all families identified was autosomal dominant.…”

Section: Introductionmentioning

confidence: 96%

“…A c.854C>T mutation in TFG that causes p.(Pro285Leu) was identified in all HMSN‐P families of the Far East and in one of the Iranian families. A different mutation in TFG (c.806G>T) that causes p.(Gly269Val) was identified in the second Iranian HMSN‐P pedigree (Khani et al, ). Interestingly, the same p.(Gly269Val)‐causing mutation had recently been reported as cause of CMT2 in a Taiwanese pedigree (Tsai et al, ).…”

Section: Introductionmentioning

confidence: 99%

Continuum of phenotypes in hereditary motor and sensory neuropathy with proximal predominance and Charcot–Marie–Tooth patients with TFG mutation

Khani

Taheri

Shamshiri

et al. 2019

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

Charcot-Marie-Tooth (CMT) is a common neuropathy, and hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) is a recently described rare neuromuscular disease. Although many genes have been implicated for CMT, TFG is the only known HMSN-P-causing gene. Within the framework of diagnostic criteria, clinical variation is evident among CMT-diagnosed and also HMSN-P-diagnosed individuals. Mutations that cause p.(Pro285Leu) and p.(Gly269Val) in TFG were earlier reported as cause of HMSN-P in two Iranian pedigrees. Here, we report the identification of p.(Gly269Val) in TFG as cause of CMT in a large Iranian pedigree. The clinical features of patients of the three pedigrees are presented and critically compared. Similarities between the two HMSN-P-diagnosed pedigrees with different TFG mutations, and differences between the two differentially diagnosed pedigrees with the same p.(Gly269Val) mutation were evident. The clinical features of the HMSN-P pedigree with the p.(Pro285Leu) and the CMT pedigree with the p.(Gly269Val) mutation were clearly congruent with the respective diagnoses, whereas the features of the HMSN-P-diagnosed pedigree with the p.(Gly269Val) were intermediate between the other two pedigrees. It is therefore suggested that the clinical features of the three Iranian pedigrees with TFG mutations and diagnosed with HMSN-P or CMT represent a continuum.

show abstract

“…7 Metabolic impairment due to the presence of altered mitochondrial network and inner membrane potential was proposed in TFG-related infantile neuroaxonal dystrophy "plus" syndrome. 8 Mutations in TFG have been reported to be associated with several distinct neurologic diseases, including the p. Pro285Leu variant-associated hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) in Japanese Okinawa origin families 9,10 and Iranian families, 11 the p.Gly269Val variant-associated autosomal dominant type of Charcot-Marie-Tooth disease type 2 (CMT2) in a Taiwanese family 12 and HMSN-P in a single Iranian family, 13 the homozygous variant c.316C > T associated with a complicated hereditary spastic paraplegia in Indian families 14,15 and infantile neuroaxonal dystrophy "plus" syndrome in a Italian family. 8 Two missense mutations associated with sporadic amyotrophic lateral sclerosis were discovered.…”

Section: Introductionmentioning

confidence: 99%

Sural nerve pathology in TFG‐associated motor neuron disease with sensory neuropathy

Meng

et al. 2019

Neuropathology

View full text Add to dashboard Cite

The tropomyosin‐receptor kinase fused gene (TFG) functions in vesicles formation and egress at the endoplasmic reticulum (ER). A heterozygous missense mutation c.854C > T (p.Pro285Leu) within TFG has been reported as causative for hereditary motor and sensory neuropathy with proximal predominance. Here, we describe two unrelated Chinese pedigrees with 13 affected members harboring the same variant. The clinical, electrophysiological and pathological findings are consistent with motor neuron disease with sensory neuropathy. The main symptoms were painful muscle cramps, slowly progressive proximal predominant weakness, muscle atrophy, fasciculation and distal sensory disturbance. Electromyography revealed widespread denervation and reinnervation. Sural nerve biopsy revealed severe loss of myelinated fibers. Electron microscopy revealed aggregation of ER with enlarged lumen and small vesicles in the remaining myelinated and unmyelinated axons. The mitochondria are smaller in Schwann cells and axons. Some unmyelinated axons showed disappearance of neurofilament and microtubular structures. This is the first report of c.854C > T mutation within TFG in Chinese population. Our findings not only extend the geographical and phenotypic spectrum of TFG‐related neurological disorders, but also confirm the abnormalities of ER and mitochondria in sural nerves.

show abstract

Identification of novel TFG mutation in HMSN-P pedigree: Emphasis on variable clinical presentations

Cited by 11 publications

References 22 publications

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

Continuum of phenotypes in hereditary motor and sensory neuropathy with proximal predominance and Charcot–Marie–Tooth patients with TFG mutation

Sural nerve pathology in TFG‐associated motor neuron disease with sensory neuropathy

Contact Info

Product

Resources

About