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


ABSTRACT:

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.

SUBMITTER: Hsiao CT 

PROVIDER: S-EPMC11251477 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Hsiao Cheng-Tsung CT   Tsai Tzu-Yun TY   Shen Ting-Yi TY   Tsai Yu-Shuen YS   Liao Yi-Chu YC   Lee Yi-Chung YC   Tsai Pei-Chien PC  

Annals of clinical and translational neurology 20240604 7


<h4>Objective</h4>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.<h4>Methods</h4>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  ...[more]

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