Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with...

Area of Science:

• Genetics
• Neuroscience
• Biochemistry

Background:

• Protein disulfide isomerase (PDI) proteins, part of the thioredoxin superfamily, are crucial for protein folding via disulfide bond formation/rearrangement in the endoplasmic reticulum.
• PDIs are also implicated in cellular stress response pathways.

Purpose of the Study:

• To investigate the genetic basis of a specific brain malformation syndrome in consanguineous families.
• To identify the causative gene and variant underlying microlissencephaly and associated neurodevelopmental deficits.

Main Methods:

• Whole exome sequencing was performed on DNA from eight children across four families presenting with microlissencephaly.
• Analysis included assessment for repeat expansions and segregation analysis to confirm variant causality.

Main Results:

• An identical homozygous variant (c.500G>A) in the TMX2 gene, encoding thioredoxin-related transmembrane protein 2, was identified and segregated with the disease in all families.
• This TMX2 variant impacted mRNA stability and was associated with severe microlissencephaly, global developmental delay, intellectual disability, and epilepsy.
• Patients did not exhibit C9ORF72 repeat expansions, despite TMX2's known role in regulating such toxicity.

Conclusions:

• The TMX2 c.500G>A allele is linked to recessive microlissencephaly, independent of C9ORF72 expansions.
• TMX2 is the first PDI identified as a cause of recessive disease, suggesting a critical role in protein isomerisation essential for normal brain development.