In their hunt for recessive FTD mutations, first author Rita Guerreiro and senior author John Hardy, at University College London, U.K., sought two things. They wanted a population with a high degree of consanguinity, such as first-cousin marriages, to boost the chances that people would inherit two copies of a defective gene. Second, they needed clinicians specializing in dementia who could identify people with FTD. They found ideal collaborators in Ebba Lohman and Murat Emre, of Istanbul University, whose patients included people from small villages where cousin marriages are common. The Turkish authors provided blood samples from 44 people with FTD, including four for whom a consanguineous pedigree was confirmed, and 23 for whom it was suspected based on marriage patterns in their hometowns.

The authors performed exome sequencing and analysis in the laboratories of Hardy and another senior author, Andrew Singleton of the National Institute on Aging in Bethesda, Maryland. They found a nonsense mutation in TREM2 in one person. Scanning the locus in the other participants, they discovered two more amino acid-substitution mutations in two other people.

Mutations in TREM2 (triggering receptor expressed on myeloid cells 2) and its ligand, TYROBP (TYRO protein tyrosine kinase binding protein), cause Nasu-Hakola disease. The disease is quite rare; in the Finnish populations where it was first described, it affects one to two people per million, according to the U.S. National Library of Medicine (reviewed in Kaneko et al., 2010). Nasu-Hakola is also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, or PLOSL. The name indicates it combines thinning and cysts in bone with white matter defects in the brain that cause personality changes, poor judgment, and eventually dementia.

The three people in the Turkish population who had Trem2 mutations exhibited white matter lesions and corresponding symptoms, but no bone problems. They started to get sick in their 20s and 30s. “They are all on the early end for frontotemporal dementia,” noted Alison Goate of Washington University in St. Louis, who was not involved in the study. The current work confirms a previous report that TREM2 mutations caused early-onset dementia without affecting bone in another family (Chouery et al., 2008).

The researchers have no idea why TREM2 affects bone only sometimes, but the variable presentation is not entirely surprising. “A lot of what we are finding by exome sequencing is genes that we have found before, but just that the phenotypes are wider,” Hardy said. For example, another team found that mutations in valosin-containing protein can create not only the panoply of symptoms that is IBMPFD—inclusion body myopathy, Paget’s disease, and frontotemporal dementia—but also motor neuron disease (see ARF related news story on Johnson et al., 2010).

At this point, scientists know little about what TREM2 does, either in health or disease. It normally dampens the immune response of microglia, but could have other jobs. The three mutations in the Turkish FTD cases all appear to cause a loss of protein function. “The pathway that TREM2 is the first member of simply does not start,” Hardy said. That pathway is not fully understood, but intriguingly, TREM2 appears to work with colony stimulating factor 1 receptor (CSF1R), which, when mutated, also causes white matter disease with dementia (see ARF related news story on Rademakers et al., 2011).

Immunity, inflammation, and phagocytosis are all possible activities that might suffer when there is a lack of TREM2, Guerreiro said. Another FTD gene, progranulin, is also involved in inflammation, Goate noted (see ARF related news story on Yin et al., 2010). Altered inflammation could turn out to be a common theme in FTD, she speculated. Yet again, the involvement of white matter in the TREM2 cases suggests that oligodendrocytes could also be affected, said Zbigniew Wszolek of the Mayo Clinic in Jacksonville, Florida, who was not involved in the study.

Goate and Wszolek do not anticipate that TREM2 mutations will underlie many FTD cases outside of consanguineous families. Early onset might indicate TREM2 involvement, Goate added. Another reason to suspect TREM2 or TYROBP mutations would be white matter pathology, which is not typical for FTD, the authors noted in their paper. Wszolek also hypothesized that mild TREM2 variants that do not completely abolish the protein’s function might turn out to be risk factors for neurodegenerative diseases such as Alzheimer’s or amyotrophic lateral sclerosis. Significant portions of genetic risk for both diseases remain unexplained to date.—Amber Dance.

Reference:
Guerreiro RJ, Lohmann E, Brás JM, Gibbs JR, Rohrer JD, Gurunlian N, Dursun B, Gilgic B, Hanagasi H, Gurvit H, Emre M, Singleton A, Hardy J. Using exome sequencing to reveal mutations in TREM2 presenting as frontotemporal dementia-like syndrome without bone involvement. Arch Neurol. 2012 Oct 8;1-7. Abstract