Novel <i>TFG</i> mutation causes autosomal-dominant spastic paraplegia and defects in autophagy.

Abstract

Mutations in the tropomyosin receptor kinase fused (<i>TFG</i>) 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. 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 <i>TFG</i> mutation in a large Chinese family with HSP. Additionally, another family diagnosed with HMSN-P and carrying the reported <i>TFG</i> 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 <i>TFG</i> mutations. A novel heterozygous <i>TFG</i> 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 <i>TFG</i> 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. Our findings suggest that autophagy impairment may serve as a common pathomechanism among different clinical phenotypes caused by <i>TFG</i> mutations. Consequently, targeting autophagy may facilitate the development of a uniform treatment for TFG-related neurological disorders.