Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with...

Area of Science:

• Neurogenetics
• Molecular Neurology
• Cell Biology

Background:

• Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal-dominant neurological disorder.
• It presents with diverse clinical symptoms affecting the central nervous system white matter.

Purpose of the Study:

• To identify the genetic cause of HDLS.
• To elucidate the underlying molecular mechanisms of the disease.

Main Methods:

• Genome-wide linkage analysis and exome sequencing were employed.
• In vitro functional assays assessed colony stimulating factor 1 receptor (CSF1R) activity.

Main Results:

• Fourteen distinct mutations in the CSF1R gene were identified in 14 HDLS families.
• Mutations were located in the tyrosine kinase domain, leading to impaired CSF1R autophosphorylation.
• An additional CSF1R mutation was found in an individual with corticobasal syndrome.

Conclusions:

• Mutations in CSF1R are a primary cause of HDLS.
• The findings suggest HDLS results from a partial loss of CSF1R function.
• Microglial dysfunction, mediated by CSF1R, plays a critical role in HDLS pathogenesis.