title: CSF1R mutations link POLD and HDLS as a single disease entity.
abstract: OBJECTIVE
  Pigmented orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) are rare neurodegenerative disorders characterized by cerebral white matter abnormalities, myelin loss, and axonal swellings. The striking overlap of clinical and pathologic features of these disorders suggested a common pathogenesis; however, no genetic or mechanistic link between POLD and HDLS has been established. Recently, we reported that mutations in the colony-stimulating factor 1 receptor (CSF1R) gene cause HDLS. In this study, we determined whether CSF1R mutations are also a cause of POLD.
  
  
  METHODS
  We performed sequencing of CSF1R in 2 pathologically confirmed POLD families. For the largest family (FTD368), a detailed case report was provided and brain samples from 2 affected family members previously diagnosed with POLD were re-evaluated to determine whether they had HDLS features. In vitro functional characterization of wild-type and mutant CSF1R was also performed.
  
  
  RESULTS
  We identified CSF1R mutations in both POLD families: in family 5901, we found c.2297T>C (p.M766T), previously reported by us in HDLS family CA1, and in family FTD368, we identified c.2345G>A (p.R782H), recently reported in a biopsy-proven HDLS case. Immunohistochemical examination in family FTD368 showed the typical neuronal and glial findings of HDLS. Functional analyses of CSF1R mutant p.R782H (identified in this study) and p.M875T (previously observed in HDLS), showed a similar loss of CSF1R autophosphorylation of selected tyrosine residues in the kinase domain for both mutations when compared with wild-type CSF1R.
  
  
  CONCLUSIONS
  We provide the first genetic and mechanistic evidence that POLD and HDLS are a single clinicopathologic entity.
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Alexandra M
authors: AM
authors: Nicholson
authors: Matt C
authors: MC
authors: Baker
authors: Nicole A
authors: NA
authors: Finch
authors: Nicola J
authors: NJ
authors: Rutherford
authors: Christian
authors: C
authors: Wider
authors: Neill R
authors: NR
authors: Graff-Radford
authors: Peter T
authors: PT
authors: Nelson
authors: H Brent
authors: HB
authors: Clark
authors: Zbigniew K
authors: ZK
authors: Wszolek
authors: Dennis W
authors: DW
authors: Dickson
authors: David S
authors: DS
authors: Knopman
authors: Rosa
authors: R
authors: Rademakers
mesh_terms: D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000175:diagnosis / Q000235:genetics*; D056784:Leukoencephalopathies / Q000175:diagnosis / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010859:Pigmentation Disorders / Q000175:diagnosis / Q000235:genetics*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics*
chemical_list: D016186:Receptor, Macrophage Colony-Stimulating Factor