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

Abstract

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.

Keywords: Colony-stimulating factor 1 receptor; adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; hereditary diffuse leukoencephalopathy with spheroids; leukoencephalopathy; mutation.

Figure 1

The pedigree of the family with ALSP is shown. There were three generations in this family. Affected patients are represented by filled black symbols. An arrowhead indicates the proband. Red symbols represent carriers of the c.2319+1C>A mutation. Open symbols indicate obligate gene carriers currently without symptoms. Diagonal lines through symbols denote deceased individuals.

Figure 2

The imaging findings in the patients with ALSP on MRI are shown. MRI findings in the proband (II-3) are shown in (A-D). T2 sequencing showed hyperintensity in the deep and periventricular white matter, cavum septum pellucidum, and cavum vergae (A). FLAIR imaging sequencing showed typical leukoaraiosis (B). Sagittal T1WI sequencing showed the thin corpus callosum (C). DWI sequencing showed restricted diffusion in the splenium of the corpus callosum (D). MRI findings in patient 2 (II-2) are shown in (E, F). DWI sequencing demonstrated restricted diffusion in the punctate areas (E), and these lesions were persistent for more than 10 months (F).

Figure 3

The mutant variant of the CSF1R gene was validated in the family. The mutation c.2319+1C>A was found in six family members, including I-1, II-2, II-3, II-5, III4, and III5. Control represents a healthy individual.

Figure 4

mRNA expression of the CSF1R gene in peripheral blood. The CSF1R gene mRNA expression was measured by quantitative PCR with different primers for the different segmentation of the CSF1R gene mRNA in patient 2 (II-2, A). The CSF1R gene mRNA expression was measured in six control subjects and four individuals carrying the novel splicing mutation using huCSF1R1416 (B).