DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• Sphingolipids are crucial for cell membranes and neurological functions like myelination.
• Defects in sphingolipid metabolism are linked to neurological diseases, but the full scope is unknown.

Purpose of the Study:

• To identify and characterize a novel human sphingolipid metabolism disorder using integrated genomics and lipidomics.

Main Methods:

• Whole-exome sequencing identified a DEGS1 variant in a patient with a multisystem neurological disorder.
• Lipidomics analysis revealed increased dihydroceramides and an atypical sphingosine isomer in patients and DEGS1-deficient cells.

Main Results:

• A homozygous p.Ala280Val variant in DEGS1, crucial for ceramide synthesis, was identified.
• Patient cells showed an 80% reduction in DEGS1 enzymatic activity and increased dihydro sphingolipids.
• A potentially neurotoxic sphingosine isomer was detected in patient plasma and cells with mutant DEGS1.

Conclusions:

• DEGS1 dysfunction is identified as the cause of a sphingolipid disorder.
• This disorder is characterized by hypomyelination and degeneration of the central and peripheral nervous systems.