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Related Concept Videos

Point and Frameshift Mutations01:30

Point and Frameshift Mutations

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Point mutations are genetic alterations involving the change of a single nucleotide base pair in DNA. Depending on how the alteration affects protein synthesis, they can lead to various consequences.Point mutations fall into the following types:Silent mutations occur when a nucleotide change does not alter the amino acid sequence due to the redundancy of the genetic code. For instance, changing ACC to ACA still encodes threonine, leaving the protein function unaffected. This occurs because...
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Cystic fibrosis (CF), an autosomal recessive disorder, significantly affects the function of exocrine glands. This genetically inherited disease is characterized by the production of thick and sticky mucus, which can severely affect various organs and systems in the body.
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Novel Frameshift Deletion Pathogenic Variant Characterization in Tuberous Sclerosis-2 Using Exome Sequencing and

Mahmood Fadaie1, Sajjad Biglari2, Hassan Vahidnezhad3,4,5

  • 1Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Biochemical Genetics
|November 11, 2025
PubMed
Summary

Researchers identified a new TSC2 gene mutation causing tuberous sclerosis complex (TSC). This frameshift deletion impacts tuberin protein structure and function, offering insights for potential mTOR pathway therapies.

Keywords:
TSC2Exome sequencingMolecular dynamics simulationTuberous sclerosisTuberous sclerosis complex 2 protein

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Area of Science:

  • Genetics
  • Biochemistry
  • Computational Biology

Background:

  • Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in TSC1 or TSC2 genes.
  • Mutations in TSC2 are associated with more severe symptoms and earlier onset.
  • Accurate genetic diagnosis is crucial for understanding disease mechanisms and patient management.

Purpose of the Study:

  • To identify and characterize a novel pathogenic variant in the TSC2 gene.
  • To investigate the structural and functional consequences of the identified variant using computational methods.
  • To evaluate the utility of exome sequencing in diagnosing TSC and informing genetic counseling.

Main Methods:

  • Exome sequencing (ES) was employed to detect the causative variant.
  • Sanger sequencing and cosegregation analysis confirmed the variant.
  • GROMACS software was used for molecular dynamics (MD) simulations to assess the variant's impact on tuberin protein structure and function.
  • Variant interpretation followed the American College of Medical Genetics and Genomics (ACMG) guidelines.

Main Results:

  • A novel de novo frameshift deletion variant (c.3647_3651del, p.Leu1216Profs*16) was identified in the TSC2 gene of a 12-year-old male patient with TSC symptoms.
  • The mutation, located in exon 31, meets ACMG criteria for pathogenicity.
  • MD simulations revealed that the mutation disrupts the GAP domain, breaks hydrogen bonds, reduces solvent exposure, and alters tuberin's stability and conformational dynamics.

Conclusions:

  • Exome sequencing is an effective tool for TSC diagnosis and genetic counseling.
  • Computational analysis provides valuable molecular insights into TSC pathogenesis.
  • The identified TSC2 variant's effects suggest potential therapeutic strategies targeting the mTOR pathway, such as using mTOR inhibitors.