Novel mutation causes autosomal-dominant spastic paraplegia and defects in autophagy.

Background: Mutations in the tropomyosin receptor kinase fused () 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 mutation in a large Chinese family with HSP. Additionally, another family diagnosed with HMSN-P and carrying the reported 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 mutations.

Results: A novel heterozygous 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 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 mutations. Consequently, targeting autophagy may facilitate the development of a uniform treatment for TFG-related neurological disorders.