Article Text

Download PDFPDF
Original research
Novel TFG mutation causes autosomal-dominant spastic paraplegia and defects in autophagy
  1. Ling Xu1,
  2. Yaru Wang1,
  3. Wenqing Wang1,
  4. Rui Zhang1,
  5. Dandan Zhao1,
  6. Yan Yun2,
  7. Fuchen Liu1,
  8. Yuying Zhao1,
  9. Chuanzhu Yan1,
  10. Pengfei Lin1
  1. 1Department of Neurology and Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
  2. 2Department of Radiology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
  1. Correspondence to Professor Pengfei Lin, Department of Neurology and Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; lpfsdu{at}foxmail.com; Professor Yuying Zhao; zyy72{at}126.com

Abstract

Background Mutations in the tropomyosin receptor kinase fused (TFG) gene are associated with various neurological disorders, including autosomal recessive hereditary spastic paraplegia (HSP), autosomal dominant hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) and autosomal dominant type of Charcot-Marie-Tooth disease type 2.

Methods Whole genome sequencing and whole-exome sequencing were used, followed by Sanger sequencing for validation. Haplotype analysis was performed to confirm the inheritance mode of the novel TFG mutation in a large Chinese family with HSP. Additionally, another family diagnosed with HMSN-P and carrying the reported TFG mutation was studied. Clinical data and muscle pathology comparisons were drawn between patients with HSP and patients with HMSN-P. Furthermore, functional studies using skin fibroblasts derived from patients with HSP and patients with HMSN-P were conducted to investigate the pathomechanisms of TFG mutations.

Results A novel heterozygous TFG variant (NM_006070.6: c.125G>A (p.R42Q)) was identified and caused pure HSP. We further confirmed that the well-documented recessively inherited spastic paraplegia, caused by homozygous TFG mutations, exists in a dominantly inherited form. Although the clinical features and muscle pathology between patients with HSP and patients with HMSN-P were distinct, skin fibroblasts derived from both patient groups exhibited reduced levels of autophagy-related proteins and the presence of TFG-positive puncta.

Conclusions Our findings suggest that autophagy impairment may serve as a common pathomechanism among different clinical phenotypes caused by TFG mutations. Consequently, targeting autophagy may facilitate the development of a uniform treatment for TFG-related neurological disorders.

  • genetics
  • mutation
  • neuromuscular diseases

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Data are available upon reasonable request.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Data are available upon reasonable request.

View Full Text

Footnotes

  • YZ and PL contributed equally.

  • Contributors CY, PL and LX contributed to study conception and design. LX drafted the manuscript text and prepared the figures. All authors contributed to patient clinical data and sequencing data acquisition and analysis, and manuscript review and revision. PL acts as a guarantor.

  • Funding This study was funded by the National Natural Science Foundation of China (Grant No. 82271436), Shandong Provincial Natural Science Foundation (Grant No. ZR2022MH190) and Qingdao Science and Technology Benefit People Demonstration Guide Special Project (Grant/Award Number: 22-8-7-smjk-1-nsh).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.