Functional characterization of a novel CSF1R mutation causing hereditary diffuse leukoencephalopathy with spheroids.

Area of Science:

• Neuroimmunology
• Genetics
• Cell Biology

Background:

• Colony-stimulating factor 1 receptor (CSF1R) is crucial for monocyte/macrophage and microglia function.
• Mutations in the CSF1R gene are linked to hereditary diffuse leukoencephalopathy with spheroids (HDLS), a severe microgliopathy causing early-onset dementia.
• HDLS is characterized by autosomal dominant inheritance and high lethality.

Observation:

• A 44-year-old female patient with a complex neuropsychiatric condition underwent interdisciplinary assessment and CSF1R gene sequencing.
• Flow cytometry was used to analyze cell surface CSF1 receptor levels and autophosphorylation in peripheral blood monocytes.
• Monocyte subpopulations were monitored throughout the disease progression.

Findings:

• A novel heterozygous deletion-insertion mutation (c.2527_2530delinsGGCA, p.(Ile843_Leu844delinsGlyIle)) was identified in the CSF1R gene of the patient.
• Elevated cell surface CSF1 receptor levels and increased Tyr723 autophosphorylation indicated enhanced receptor activity.
• A notable shift in monocyte subpopulations was observed during the course of the disease.

Implications:

• The identified mutation suggests a gain-of-function mechanism for CSF1R in HDLS.
• The altered composition of peripheral innate immune cells is a key feature associated with the mutation.
• Targeting CSF1R with tyrosine kinase inhibitors may offer a potential therapeutic strategy for HDLS, building on evidence from neurodegenerative disease models.