Reduced secretion and altered proteolytic processing caused by missense mutations in progranulin

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Progranulin (GRN) is a secreted growth factor crucial for cellular functions.
• Loss-of-function mutations in GRN are a primary cause of frontotemporal lobar degeneration (FTLD) with TDP-43 pathology.
• While nonsense mutations reduce GRN expression, the pathogenicity of missense mutations remains unclear.

Purpose of the Study:

• To investigate the functional impact of novel GRN missense mutations.
• To determine if identified GRN variants contribute to neurodegenerative disease risk.

Main Methods:

• Identified a double missense mutation (p.D33E/p.G35R) in an FTLD patient.
• Analyzed the secretion efficiency and protein processing of GRN variants (p.D33E/p.G35R, p.C105R, p.V514M) using biochemical and cell biological methods.

Main Results:

• The GRN p.D33E/p.G35R and p.C105R variants exhibited reduced secretion efficiency.
• Loss of a conserved cysteine residue (p.C105R) impaired protein folding and altered proteolytic processing.
• Identified GRN variants may lead to partial loss-of-function.

Conclusions:

• The identified GRN missense mutations can impair protein secretion and processing.
• These variants may represent low-penetrant risk factors for neurodegenerative diseases, distinct from null mutations.