Molecular phenotypes segregate missense mutations in SLC13A5 Epilepsy

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• SLC13A5 Epilepsy, also known as EIEE25, is a severe neurological disorder caused by loss-of-function mutations in the SLC13A5 gene.
• The SLC13A5 gene encodes the sodium-coupled citrate transporter (NaCT), crucial for neuronal citrate uptake.
• Current understanding of the molecular mechanisms underlying SLC13A5 Epilepsy and potential cures remains limited.

Approach:

• Mechanistically classified the molecular phenotypes of six distinct SLC13A5 mutations.
• Assessed citrate transport, protein expression, localization, and glycosylation.
• Analyzed mRNA levels and protein half-lives to identify post-translational defects.

Key Points:

• Mutations C50R, T142M, and T227M impair citrate transport without affecting cell surface expression.
• Mutations G219R, S427L, and L488P result in reduced protein expression, ER retention, and impaired transport.
• Class II mutations exhibit defects in protein folding, indicated by immature glycosylation and shortened half-lives.

Conclusions:

• Identified two distinct classes of molecular defects in SLC13A5 mutations, impacting NaCT function and trafficking.
• Findings provide a comprehensive understanding of SLC13A5 Epilepsy at the molecular level.
• Different therapeutic strategies are required to address the distinct mutation classes, aiming to restore transport or correct protein folding defects.