SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Sphingolipids are vital for nervous system function, particularly in myelin.
• Serine palmitoyltransferase (SPT) regulates sphingolipid synthesis, with SPTSSA as an activating subunit.
• ORMDL proteins provide feedback inhibition to prevent excessive sphingolipid levels.

Purpose of the Study:

• Investigate the role of SPTSSA variants in hereditary spastic paraplegia (HSP).
• Determine how SPTSSA variants affect SPT activity and sphingolipid homeostasis.
• Establish the link between impaired sphingolipid regulation and neurological dysfunction.

Main Methods:

• Exome sequencing to identify SPTSSA variants in patients with complex HSP.
• Functional studies in human embryonic kidney cells and patient fibroblasts.
• In vivo studies using Drosophila models.

Main Results:

• Identified two pathogenic SPTSSA variants in three individuals with HSP, sensorineural hearing loss, and cognitive dysfunction.
• These variants impaired ORMDL-mediated feedback inhibition of SPT.
• Biochemical and Drosophila studies confirmed excessive sphingolipid synthesis due to dysregulated SPT activity.

Conclusions:

• SPTSSA variants are pathogenic and cause HSP.
• Impaired negative regulation of SPT by ORMDLs leads to excessive sphingolipid synthesis.
• Dysregulated sphingolipid metabolism contributes to early brain development and function defects.