From HDLS to BANDDOS: fast-expanding phenotypic spectrum of disorders caused by mutations in CSF1R

Area of Science:

• Neurogenetics
• Molecular Biology
• Developmental Biology

Background:

• Colony-stimulating factor 1 receptor (CSF1R) is crucial for monocyte/macrophage lineage cells, including microglia and osteoclasts.
• Mono-allelic CSF1R mutations cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset neurodegenerative disease.
• Bi-allelic CSF1R mutations result in a more severe phenotype, brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS).

Purpose of the Study:

• To review monogenic disorders associated with CSF1R mutations.
• To analyze the mutational spectra of CSF1R-related diseases.
• To propose a dose-dependent model for CSF1R genotype-phenotype correlations.

Main Methods:

• Literature review of CSF1R-related genetic disorders.
• Analysis of reported CSF1R mutations and associated phenotypes.
• Development of a conceptual model explaining genotype-phenotype relationships.

Main Results:

• CSF1R mutations are linked to a spectrum of neurodevelopmental and neurodegenerative disorders.
• Mono-allelic mutations cause HDLS, while bi-allelic mutations cause the more severe BANDDOS, including brain malformations and skeletal dysplasia.
• Incomplete BANDDOS phenotypes are observed with specific bi-allelic missense mutations.

Conclusions:

• CSF1R mutation severity correlates with the number of affected alleles.
• A dose-dependent model effectively explains the diverse clinical presentations of CSF1R disorders.
• Understanding CSF1R's role is critical for diagnosing and potentially treating these rare genetic conditions.