CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids

Abstract

Mutations in the colony stimulating factor 1 receptor (CSF1R) have recently been discovered as causal for hereditary diffuse leukoencephalopathy with axonal spheroids. We identified a novel, heterozygous missense mutation in CSF1R [c.1990G > A p.(E664K)] by exome sequencing in five members of a family with hereditary diffuse leukoencephalopathy with axonal spheroids. Three affected siblings had characteristic white matter abnormalities and presented with progressive neurological decline. In the fourth affected sibling, early progression halted after allogeneic haematopoietic stem cell transplantation from a related donor. Blood spot DNA from this subject displayed chimerism in CSF1R acquired after haematopoietic stem cell transplantation. Interestingly, both parents were unaffected but the mother's blood and saliva were mosaic for the CSF1R mutation. Our findings suggest that expression of wild-type CSF1R in some cells, whether achieved by mosaicism or chimerism, may confer benefit in hereditary diffuse leukoencephalopathy with axonal spheroids and suggest that haematopoietic stem cell transplantation might have a therapeutic role for this disorder.

Keywords: dementia; leukodystrophy; neurodegeneration; neuroinflammation; whole exome sequencing.

Mutations in CSF1R, which encodes colony stimulating factor 1 receptor, cause hereditary diffuse leukoencephalopathy with axonal spheroids. Eichler et al. describe a family in which the mother is unaffected despite carrying a CSF1R mutation in ~20% of blood cells. Haematopoietic stem cell transplantation halted disease progression in her affected daughter.

Figure 1

MRI findings in HDLS. Affected sibling Patient II-2: 60-year-old male with progressive cognitive deterioration and motor problems. His MRI shows enlarged ventricles with diffuse patchy white matter lesions more prominent in the frontal (A, white arrows) than in the posterior regions (B, black arrows). There is no contrast enhancement present.

Figure 2

Genomic and protein localization of novel CSF1R mutation. (A) Genomic organization of the 60 kb CSF1R gene with 22 exons (vertical hatches); (B) exon structure of the human CSF1R cDNA, with start codon (ATG) and stop codon (TGA) shown. Arrow shows position of c.1990G > A, p.(E664K) mutation in exon 15. (C) Domain structure of the CSF1R protein showing the immunoglobulin domains (Ig) and the protein tyrosine kinase domain (PTK), interrupted by the kinase insert at amino acid positions 670-740 (shaded). (D) The position of the p.E664K mutation adjacent to the kinase insert within the PTK domain. (E) Alignment for the parts of the PTK domain surrounding p.E664K, including human CSF1/PDGF receptor family members and multiple CSF1R homologues.

Figure 3

Pedigree of family with HDLS and sequence at the novel CSF1R p.E664K mutation site. Filled circles (black or hashed pattern) indicate affected family members. Transplanted individual (Patient II-1) is labelled with ‘HSCT’ and filled with a hashed pattern to indicate a milder clinical course. Deceased individual is marked by a slash. Sanger sequence traces of DNA surrounding the c.1990G > A, p.(E664K) mutation shaded in blue [reverse strand sequence corresponding to wild-type CC homozygous genotype (wt) or heterozygous CT genotype (het) are shown for each family member]. The source of DNA for each trace is listed below the trace diagram and fraction of mutant allele reads from exome sequencing or estimated by Sanger sequencing is indicated in brackets after source of DNA. Mosaicism is seen in DNA from blood and saliva from Patient I-2 (mother). Sanger trace for transplanted Patient II-1 in blood spot DNA is ∼50% (consistent with 57.5% normal allele expected based on 15% donor chimerism).