Characterization of a novel TFG variant causing autosomal recessive pure hereditary spastic paraplegia.

OBJECTIVE: TFG mutations have previously been implicated in autosomal recessive hereditary spastic paraplegia (HSP), also known as SPG57. This study aimed to investigate the clinical and molecular features of TFG mutations in a Taiwanese HSP cohort. METHODS: Genetic analysis of TFG was conducted in 242 unrelated Taiwanese HSP patients using a targeted resequencing panel covering the entire coding regions of TFG. Functional assays were performed using an in vitro cell model to assess the impact of TFG variants on protein function. Additionally, other representative TFG mutant proteins were examined to understand the broader implications of TFG mutations in HSP. RESULTS: The study identified a novel homozygous TFG c.177A>C (p.(Lys59Asn)) variant in a family with adolescent-onset, pure form HSP. Functional analysis revealed that the Lys59Asn TFG variant, similar to other HSP-associated TFG mutants, exhibited a low affinity between TFG monomers and abnormal assembly of TFG homo-oligomers. These structural alterations led to aberrant intracellular distribution, compromising TFG's protein secretion function and resulting in decreased cellular viability. INTERPRETATION: These findings confirm that the homozygous TFG c.177A>C (p.(Lys59Asn)) variant is a novel cause of SPG57. The study expands our understanding of the clinical and mutational spectrum of TFG-associated diseases, highlighting the functional defects associated with this specific TFG variant. Overall, this research contributes to the broader comprehension of the genetic and molecular mechanisms underlying HSP.

Genetic and Functional Analysis of Glycosyltransferase 8 Domain-Containing Protein 1 in Taiwanese Patients With Amyotrophic Lateral Sclerosis.

BACKGROUND AND OBJECTIVES: To investigate the frequency, spectrum, and molecular functional effect of glycosyltransferase 8 domain-containing protein 1 (GLT8D1) variations in Taiwanese patients with amyotrophic lateral sclerosis (ALS). METHODS: We performed genetic analyses of GLT8D1 in 410 unrelated patients with ALS by Sanger sequencing. The 410 patients were selected from a cohort of 477 unrelated patients with ALS after excluding variations in common ALS disease genes. Functional effects of the GLT8D1 variation were investigated by in vitro functional analysis. RESULTS: We identified a novel heterozygous missense variation in GLT8D1, p.I290M (c.870C>G), in 1 single patient with familial ALS. The patient with the p.I290M variation had a spinal-onset ALS with disease onset at age 60 years and a survival of 6 years. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity. DISCUSSION: GLT8D1 variations account for 0.2% (1/477) of the patients with ALS in Taiwan. These findings expand the spectrum of GLT8D1 variation and support the pathogenic role of GLT8D1 variations in ALS.