An international consortium led by researchers at the Mayo Clinic in Jacksonville, Florida, has found the gene responsible for hereditary diffuse leukoencephalopathy with spheroids (HDLS). A rare disease that results in dementia and death typically between ages 40 and 60, HDLS presents with variable clinical symptoms, making diagnosis difficult. Patients are sometimes diagnosed as having Alzheimer’s disease, frontotemporal degeneration, or multiple sclerosis until pathological examination on autopsy clarifies what they really had. The new study, published December 25, 2011, in Nature Genetics, paves the way for a genetic test for the disease. “The number of identified cases will probably go up in the next few years. This disease is rare but underdiagnosed,” said Hans Klünemann of the University of Regensburg in Germany, who was not involved in the study. He added, however, that it may be several years before the discovery translates into a therapy for this disorder.

Senior authors Zbigniew Wszolek and Dennis Dickson, both at the Mayo Clinic in Jacksonville, spearheaded the international effort to find the genetic cause of HDLS, which is inherited in an autosomal-dominant manner. Wszolek and Dickson enlisted researchers from 12 institutions in five countries to provide DNA samples from patients and their families. “We were able to obtain samples from 14 families. The criterion was that each family had to have had at least one patient with a pathological confirmation,” said first author Rosa Rademakers, also at Mayo. Rademakers took the lead on the genetic analysis of the collected samples.

One of the largest families, from Virginia, was chosen for genomewide linkage analysis. Rademakers and colleagues identified one locus on chromosome 5 that showed a significant association with the disease. They then sequenced all the exons in this region in DNA samples from two patients of the kindred. They identified two mutations: one in the gene encoding 5-hydroxytryptamine receptor 4 (HTR4) and one in the gene for the colony stimulating factor 1 receptor (CSF1R). When the researchers looked for these mutations in affected people from the other 13 families, they found mutations in the CSF1R gene—in all the patients. “Our hypothesis was that we would find multiple genes affected in HDLS since the clinical phenotype is so variable,” said Rademakers. “The surprise was that the same gene was mutated in all our families.”

The CSF1R protein is a tyrosine kinase transmembrane receptor primarily present in microglia, the immune cells of the brain. Binding of the ligand CSF1 to CSF1R causes the receptor to form homodimers and subsequently autophosphorylate at several tyrosine residues in the kinase region. The HDLS patients in this study had different mutations but all popped up in that domain. When Rademakers and colleagues transfected cultured cells with wild-type and mutant CSF1R and then stimulated the cells with CSF1, only the wild-type receptors became autophosphorylated. These preliminary results suggest that the mutation might affect CSF1R’s kinase function and presumably microglia activity, but more work will be needed to understand this mechanism.

The discovery does not suggest an immediate therapeutic intervention. “Even if there is no therapy, it will be helpful for patients to know they have the disease so that they know what to expect down the line,” said Klünemann. “I have met patients who have spent 10 years going from doctor to doctor to find out what they have.” Having a definite diagnosis will also help exclude HDLS patients from clinical trials of Alzheimer’s or other diseases. “You don’t want to expose patients to drugs that may have toxic effects if you are not treating the right disorder,” said Rademakers.

Identifying CSF1R as the genetic cause of HDLS may shed light on another rare condition: Nasu-Hakola disease (NHD). NHD is characterized by systemic bone cysts and dementia caused by recessive, loss-of-function mutations in the DAP12-TREM2 protein complex (Paloneva et al., 2000; Paloneva et al., 2002). Recently, researchers implicated this complex in CSF1R signaling (Otero et al., 2009). Rademakers and colleagues suspect that both diseases may involve the same pathway, affecting microglia activity. “For basic researchers, this study will open up a plethora of possibilities to explore the molecular mechanism behind this disease and other microgliopathies,” said Klünemann—Laura Bonetta


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Paper Citations

  1. . Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet. 2000 Jul;25(3):357-61. PubMed.
  2. . Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet. 2002 Sep;71(3):656-62. Epub 2002 Jun 21 PubMed.
  3. . Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin. Nat Immunol. 2009 Jul;10(7):734-43. PubMed.

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Primary Papers

  1. . Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet. 2011 Dec 25; PubMed.