Neurology. Genetics · 2026
TSC2 GAP Domain V1646Cfs*7 Variant Alters Protein Stability and Interaction Networks in Tuberous Sclerosis Complex.
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Utami Kagistia Hana, Han Velda X, Mohammad Yusof Nur Amirah Bte, Ramaswamy Yazhini, Feng Jia, Tay Stacey Kiat Hong, Langley Sarah R, Pouladi Mahmoud A
Аннотация
OBJECTIVES: Tuberous sclerosis complex (TSC) is autosomal dominant neurocutaneous disorder caused by TSC1/2 pathogenic variants. We report a child with refractory epilepsy and developmental delay who harbors a de novo TSC2 p.V1646Cfs*7 variant. To elucidate its functional consequences, we assessed the variant's effects on proteostasis, providing a framework for developing therapeutic strategies addressing the underlying molecular disruptions.
METHODS: The child was identified through genetic testing. Molecular characterization included bioinformatics prediction, protein stability assays, and mass spectrometry, which identified protein-protein interactions between control and TSC2 V1646Cfs*7. Pathway analysis and cross-referencing with autism and epilepsy databases were performed to assess functional significance.
RESULTS: The TSC2 p.V1646Cfs*7 variant produced a truncated yet initially stable protein with distinct properties. The pathogenic variant retained subcellular localization and mTOR interactions but showed accelerated degradation. Proteomic analysis revealed enrichment in RNA metabolism and mitophagy pathways, with significant overlap with autism and epilepsy-related genes.
DISCUSSION: This study expands our understanding of TSC2 variants, highlighting how altered protein stability and interaction networks contribute to disease pathology. Disruptions in RNA processing and mitochondrial homeostasis may underlie key aspects of the TSC2 phenotype. These findings highlight the potential for precision medicine in TSC and offer scalable framework for modeling other variants in syndromic disorders with uncharacterized pathogenicity.
METHODS: The child was identified through genetic testing. Molecular characterization included bioinformatics prediction, protein stability assays, and mass spectrometry, which identified protein-protein interactions between control and TSC2 V1646Cfs*7. Pathway analysis and cross-referencing with autism and epilepsy databases were performed to assess functional significance.
RESULTS: The TSC2 p.V1646Cfs*7 variant produced a truncated yet initially stable protein with distinct properties. The pathogenic variant retained subcellular localization and mTOR interactions but showed accelerated degradation. Proteomic analysis revealed enrichment in RNA metabolism and mitophagy pathways, with significant overlap with autism and epilepsy-related genes.
DISCUSSION: This study expands our understanding of TSC2 variants, highlighting how altered protein stability and interaction networks contribute to disease pathology. Disruptions in RNA processing and mitochondrial homeostasis may underlie key aspects of the TSC2 phenotype. These findings highlight the potential for precision medicine in TSC and offer scalable framework for modeling other variants in syndromic disorders with uncharacterized pathogenicity.