Genetics of FTLD : overview and what else we can expect from genetic studies
Abstract
Frontotemporal lobar degeneration ( FTLD ) comprises a highly heterogeneous group of disorders clinically associated with behavioral and personality changes, language impairment, and deficits in executive functioning, and pathologically associated with degeneration of frontal and temporal lobes. Some patients present with motor symptoms including amyotrophic lateral sclerosis. Genetic research over the past two decades in FTLD families led to the identification of three common FTLD genes (microtubule‐associated protein tau, progranulin, and chromosome 9 open reading frame 72) and a small number of rare FTLD genes, explaining the disease in almost all autosomal dominant FTLD families but only a minority of apparently sporadic patients or patients in whom the family history is less clear. Identification of additional FTLD (risk) genes is therefore highly anticipated, especially with the emerging use of next‐generation sequencing. Common variants in the transmembrane protein 106 B were identified as a genetic risk factor of FTLD and disease modifier in patients with known mutations. This review summarizes for each FTLD gene what we know about the type and frequency of mutations, their associated clinical and pathological features, and potential disease mechanisms. We also provide an overview of emerging disease pathways encompassing multiple FTLD genes. We further discuss how FTLD specific issues, such as disease heterogeneity, the presence of an unclear family history and the possible role of an oligogenic basis of FTLD , can pose challenges for future FTLD gene identification and risk assessment of specific variants. Finally, we highlight emerging clinical, genetic, and translational research opportunities that lie ahead. image Genetic research led to the identification of three common FTLD genes with rare variants ( MAPT , GRN , and C9orf72 ) and a small number of rare genes. Efforts are now ongoing, which aimed at the identification of rare variants with high risk and/or low frequency variants with intermediate effect. Common risk variants have also been identified, such as TMEM106B . This review discusses the current knowledge on FTLD genes and the emerging disease pathways encompassing multiple FTLD genes. This article is part of the Frontotemporal Dementia special issue .
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- Authors
- Pottier, C., Ravenscroft, T. A., Sanchez‐Contreras, M., & Rademakers, R.
- Affiliations
- Mayo Clinic (US)
- Mayo Clinic Jacksonville Department of Neuroscience Jacksonville FL USA
- Corresponding author
- Rademakers, Rosa
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2016-08
- Volume
- 138
- Issue
- S1
- Pages
- 32-53
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2310226166
- Cited by
- 148
- References
- 26
- Citations by year
- 2026: 4 · 2025: 15 · 2024: 7 · 2023: 9 · 2022: 11 · 2021: 23 · 2020: 17 · 2019: 20 · 2018: 20 · 2017: 16 · 2016: 6
- FWCI
- 2.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (P50 AG016574, P50 NS072187, R01 NS080882, R01 NS076471)
- ALS Therapy Alliance
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- frontotemporal lobar degeneration, risk genes, MAPT, progranulin, C9orf72, TMEM106B, rare variants, common genetic variants, disease heterogeneity, oligogenic inheritance, disease pathways, amyotrophic lateral sclerosis, genetic risk prediction
- MeSH terms
- C9orf72 Protein, Progranulins, Amyotrophic Lateral Sclerosis, Humans, Proteins, Risk Factors, tau Proteins, Intercellular Signaling Peptides and Proteins, Frontotemporal Lobar Degeneration
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