TBC1D24 truncating mutation resulting in severe neurodegeneration

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Recessive TBC1D24 gene mutations are linked to familial infantile myoclonic epilepsy and focal epilepsy with intellectual disability.
• Previous studies identified three missense mutations in TBC1D24, all resulting in loss of function.
• A family with severe, lethal epileptic encephalopathy was investigated for TBC1D24 mutations.

Purpose of the Study:

• To identify the genetic cause of a severe epileptic encephalopathy.
• To characterize novel TBC1D24 mutations and their associated transcript isoforms.
• To expand the understanding of TBC1D24-related epilepsy phenotypes.

Main Methods:

• Whole exome sequencing and Sanger sequencing of TBC1D24 were performed.
• Novel mRNA isoform structures were determined using Sanger sequencing.
• Real-time quantitative PCR was used to assess mRNA isoform abundance.

Main Results:

• A homozygous two-base pair deletion causing premature termination in TBC1D24 was identified.
• Two novel TBC1D24 transcript isoforms were discovered.
• Isoform 1 is predominantly expressed in the brain, while Isoform 2 is found in non-neural tissues (excluding muscle).

Conclusions:

• The identified mutation's severity contributes to the severe phenotype, sparing Isoform 2.
• Previously reported mutations affected both Isoform 1 and Isoform 2.
• These findings broaden the spectrum of TBC1D24-related phenotypes and transcript isoforms.