A novel dominant-negative mutation of the CSF1R gene causes adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare autosomal dominant disorder that is caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. Functional haplo-insufficiency of the CSF1R gene has been considered for the underlying genetic mechanisms. A novel mutation of CSF1R and its effects on CSF1R expression or clinical characteristics were explored in an ALSP family. Clinical data and imaging data were collected from the family members with ALSP. Peripheral blood samples were collected for DNA and RNA extraction. Whole-exome sequencing and quantitative PCR were used to identify mutations and to determine the expression of CSF1R. The family had a history of a dominant hereditary pattern. Patients in this family presented motor symptoms, emotional abnormality, or memory impairment at onset. MRI findings showed high hyperintensity signals of T2-weighted imaging in the white matter and atrophy of the corpus callosum. NOTCH3 gene sequencing ruled out the diagnosis of CADASIL. Whole-exome sequencing identified a novel splice-site mutation (c.2319+1C>A) in intron 16 of the CSF1R gene. CSF1R mRNA was significantly decreased (~15%) in the peripheral blood samples of affected patients, which was much lower than the expected 50%. Our findings not only supported the pathological implication of this splice-site mutation but also demonstrated for the first time a dominant-negative effect on CSF1R expression. This report extends the genetic spectrum of ALSP with CSF1R mutations and provides evidence for the clinical heterogeneity of ALSP. AJTR