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.
- 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.
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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.
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