MAPT gene and Frontotemporal Dementia
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Taupathy-Image source:

Frontotemporal dementia (FTD) is the second most common type of dementias. Although causes for most cases are still unknown, approximately 10-15% of the familial cases are genetic based [1]. MAPT is the earliest gene discovered as a possible causal factor for FTD. Over 40 different mutations on this gene can cause toxic aggregation of tau protein that is encoded by MAPT and eventually lead to Frontotemporal dementia. Neuropathology for FTD is heterogeneous meaning that in addition to tau, variety of proteins from 6 other genes can lead to such neurodegeneration [2]. Recent studies, revealed association between haplotypes of MAPT gene and familial Frontotemporal dementia that shines a light in early prediction of this neurodegenerative disease [3]. Additionally, based on improvements in genetics of Frontotemporal Dementia, practical use of genetic counseling for families at risk have captured the attention of neuroscientists in attempting to use this information and help prepare individuals for this disease with late onset [4].


Frontotemporal dementia (FTD) is the second most common form of Dementia for people under the age of 60-65 after Alzheimer’s disease. FTD is a neurodegenerative fatal disease with the onset of around 45-65 years of age that is caused by neuronal destruction in frontal and temporal lobes of the brain. Most salient symptoms of FTD are social conduct and personality changes [7]. While majority of FTD cases are sporadic, about 25-50% of cases have found to be caused by inheritable factors in families; namely familial FTD (FFTD)10% of FFTD cases have autosomal dominance inheritance with genetic factors that contribute towards it[2] . MAPT gene is the first discovered gene linked with Frontotemporal dementia that is located on chromosome 17 .MAPT genetic mutations can disrupt the translated product, protein tau, mostly in central nervous system and contribute towards 15-20% of familial causes of FTD [1]. This gene is also called tau gene in reference to the protein that encodes. No definite treatment has been found for FTD yet but we’ll be going into details about the mechanism of function of MAPT and its mutations relative to Frontotemporal dementia and the latest genetic discoveries.

Tau protein

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Neurofibrillary tangles of mutated tau protein-Image source:

Tau protein is the final product of MAPT gene and has a major role in causing frontotemporal neurodegeneration in some FTD patients. In a healthy individual, tau associates microtubules in neuronal cells by binding to them. Tau proteins promote microtubule assembly and disassembly as well as stabilizing and regulating the microtubules. It also contributes towards axonal transport in neurons in the CNS and is important in signal transduction [11], [7]. Because of all of such vital functions, tau proteins are essential for neuron’s integrity and any disruption in their function could lead to the pathology widely known as taupathy. In addition to FTD, taupathy, can also contribute to other neurodegenerative diseases such as Pick’s disease, corticobasal degeneration (CBD), supernuclear palsy(PSP),etc [2].
Tau protein has 6 isoforms. Two of the most important ones are 3 three-repeat (3R) and 3 four-repeat (4R) isoforms. These repeats are on the microtubule binding site of the protein and both have important functions in assisting the microtubules. These isoforms also differ in terms of number of amino acids in their amino terminal. A specific ration of 3R and 4R isoforms is essential for healthy maintenance and regulation of microtubules and any disruption could be harmful towards the neuronal cell [1], [14]

The MAPT(tau) gene

genetic structure

The locus of MAPT gene is 17q21 on chromosome 17 and it codes for protein tau in central nervous system. Familial FTD is also referred to as Frontotemporal dementia with Parkinsonism linked with chromosome 17 (FTDP-17) due to mutations that MAPT and overlap of symptoms with other neurodegenerative disorders. It’s worth mentioning that MAPT mutations have strong association with behavioral variant of FTD which has salient negative personality changes [6].
MAPT gene has 3 sections: microtubule binding site (MT site), N-terminal projection domain and C-terminal tail. Mutations that occur in this gene play major roles in FFTD taupathy. Two types of mutations are related to FFTD in MAPT gene: 1. Missense exonic mutations that mostly occur in the MT site coding the main structural part of tau protein .Such mutations account for 80% of all relative mutations. 2. Mutations that affect the pattern of alternative splicing for tau protein. MAPT gene has 3 splicing regions in exons 2, 3 and 10 which gives rise to different aforementioned isoforms. The alternative splicing of exon 10 is very important for differentiation of 3R and 4R isoforms and their rate of production [7],[1]. These second groups of mutations are mainly intronic and localized to area surrounding the exon 10 region. Both of these mutations work in a way to disable tau protein from their microtubule regulation and maintenance functions by causing imbalance in their vital 3R/4R ratio or deforming the microtubule binding region. Either way would cause damage to neuronal integrity, and internal processes as well as causing toxic aggregation of tau proteins. Both of these processes, with higher focus on the second factor cause cellular death in FFTD [7], [2] .

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Genetic structure of MAPT gene- Lyer et al, 2013

The function of N-terminal tail is that after the protein is bound to microtubule , this section projects outward and is responsible to determine the spacing between different types of microtubules. Thus, it does assist in microtubule functioning. This area has 3 isoforms but there isn’t much known about their functions. These isoforms are mapped by exon 2 and 3 in MAPT gene. It’s been found than compared with exon 3, exon 2 rises the propensity of tau proteins to be aggregated and thus contributes towards pathogenicity of FTD. C-terminal is the least well understood section both in the protein and the gene, but it’s assumed to be an indirectly regulative factor in microtubule related functions of the protein. It’s also shorter in size relative to both the MT binding region and N-terminal tail [1].

Discovered mutations

Over 40 mutations have been found on the MAPT gene that are correlated with FFTD. As mentioned, they mostly occur in the primary encoding region either in the exonic or intronic sections. Here are some examples of the novel mutations: R5H (exon 1), G55R (exon 2), Val75Ala (exon 3), L266 and K257T (exon 9), P301S (exon 10), S356T, Q336R and K369I (exon 12), R406W(exon 13), etc[1],[10],[8],[6],[7],[5]. Depending on their location on the gene, they can be either close to the N-terminal, C-terminal or on MT site. Some of the discovered genes such as P301S on exon 10 were found in patients with very early onset, in the second decade of their life, while R406W mutation on exon 13 is associated with very late onset around the age of 75. There are other differences among these genes and their association with FTD that have made such investigations an engaging topic in recent neurodegenerative studies. These mutations were mostly found from pathological examination of FTD patients who carried the genetic mutations. Most recently, animal models (especially mice) have entered this scientific field to help discover more mutation to better predict the disease in early ages [9]. Such information would be very helpful in genetic counseling that will be discussed further.

Other genes

Frontotemporal dementia has a heterogeneous pathological nature. FTD’s main neurodegenerative mechanism that kills the neurons in frontal and temporal lobes is the toxic aggregation of proteins. This heterogenicity is caused by the variety of proteins that can lead to such neurodegeneration. Pathologies of FTD are grouped under Frontotemporal lobar degeneration (FTLD) and are categorized based on the specific protein involved in the expression of the disease. There is about 5 main FTLD categories that we won’t go into much details for them: FTLD-tau, FTLD-TDP, FTLD-UPS, FTLD-IF and FTLD-ni [2] ,[9].
In addition to MAPT, there are 6 more genes that could lead to familial FTD and are scattered across different chromosomes. Some of these genes map for the same protein such as TDP protein that is encoded by either of C90RF72 (chromosome9), Progranulin(PGRN) or Vasolin containing protein gene(VCP) grouping them all under FTLD-TDP pathology. Others such as Chromatin-modifying protein gene (CHM2B), TAR DNA binding protein gene (TARDBP) and fused-in-sarcoma gene (FUS) have their own specific protein. Amongst them, MAPT, PGRN and C90RF72 are the three most common genes that cause FFTD in the patients [10], [1],[9].

MAPT Haplotypes

MAPT gene has 2 major haplotypes H1 and H2 and recently they have been the focus of studies in relation to Frontotemporal dementia and other neurodegenerative diseases. Their specific overexpression in some of the neurodegenerative diseases has made scientists wonder if they can be used as a marker for presence, onset or degree of the disease. These haplotypes have 8 SNPs and they are extended along the gene [2] . H1 and H2 differ in their transcription-related activity and how they associate with neurodegenerative diseases. Many papers have confirmed that H1 haplotype is overpresented in some neurodegeneratiove diseases including sporadic FTD, PSP and CBD [12], [3] . Investigation of H2 haplotype is relatively a more recent area of focus, but has found to be related to both Familial and sporadic FTD. H2 appears to act as a predictor of the age of onset in sporadic FTD as its expression increases in FTD patients with early onset. One study that investigated brain morphology in relation to both of MAPT haplotypes, found specific cerebral pattern (gray matter in specific) associated with over-expression of H1 haplotype that put the carriers at higher risk to develop neurodegenerative diseases[3]. Another brain imaging study illustrated that in carriers of H2 haplotype, stronger hypometabolism of glucose was seen in frontal regions compared to H1 carriers [13]. This fact couldn’t be used as a marker for duration or severity of the disease but it could be used to account for as a more severe course of disorder.
Although interesting results have been found for both haplotypes, further investigation is needed for confirmation of the results and seeking the possibility that H1 and H2 haplotypes could be used in prediction of FTD or other neurodegenerative diseases.

Genetic Counseling

Based on the newest discoveries in the area of genetics related to Frontotemporal dementia, genetic counseling has started to being used in families at risk. Generally speaking, in FFTD cases with autosomal inheritance if parents have FFTD there is 50% chance that children could have inherited the FTD [4]. Thus, genetic counseling could be a great help and predictor of what could come later in the life of the child. Since MAPT is one of the major genes that have found to be related to FTD, being genetically tested, if similar mutation was found, could help the patient ease into the process and be prepared for this disease. In order to be individually tested, comprehensive family history and matching medical records must show an autosomal dominance pattern of inheritance [4].

This area hasn’t been investigated much except for few papers, but genetic counseling has received mixed reactions among susceptible families. While about half of the families had negative thoughts about genetic counseling, the other half found this option to be helpful for them to plan for the upcoming financial costs as well as being generally prepared and knowledgeable for what’s about to come. Those who weren’t as willing to do the testing reported great deal of anxiety and depression that they wanted to avoid [4]. A paper looked into this reaction as a result of disrupted separated-individuation process in enmeshed families. They explained that this process has two main phases in childhood attachment as well as teen hood that teenagers are making their own ideas and have the tendency to be in opposition with their families. When this separation-individuation process is not successfully completed, individuals who are at risk for such neurodegenerative diseases could either be against genetic testing due to the pressure that they are under from their family, or they could become more willing to be tested because they want to be in opposition and be separated from their families [15]. Another reasoning that was found is psychological fragility of families at risk. Such families had parents with FTD that would have sudden change of personality towards a more impulsive and aggressive person that could disrupt the secure attachment between parent and the child. This disrupted pattern has many negative effects on the time being as well as further impacts on the normal developmental course of the child later in life that could cause them to avoid genetic testing for individual or family-pressured reasons as previously mentioned [4] Further investigation in genetic counseling needs to be performed not only in the area of testing acceptance but also how haplotypes and novel mutations can help.

1. Lyer, A., Lapointe, N.E., Zielke, K., Berdynski, M., Guzman, E., Barczak, A., Chodakowaska-Zebrowska, M., Barcikowska, M., Feinstein, S., & Zekanowski, C. (2013). A Novel MAPT Mutation, G55R, in a Frontotemporal Dementia Patient Leads to Altered Tau Function. PLOS One, 8(9).
2. Neumann, M., Tolnay, M., & Mackenzie, I.R. (2009). The molecular Basis of Frontotemporal Dementia. Expert Reviews in Molecular Medicine, 11(23).
3. Canu, E., Boccardi, M., Ghidoni, R., Benussi, L., Testa, C., Pievani, M., Bonetti, M., Binetti, G., & Frisoni, G.B. (2009). H1 Haplotype of the MAPT Gene is Associated With Lower Regional Gray Matter Volume in Healthy Carriers. European Journal of Human Genetics, 17(3), 287-294.
4. Quaid, K.A. (2011). Genetic Counseling for Frontotemporal Dementias. Journal of Molecular Neuroscience, 45(3), 706-709.
5. Liado, A., Ezquerra, M., Sanchez-Valle, R., Rami, L., Tolosa, E., & Molinuevo, J.L. (2007). A Novel MAPT Mutation (P301) Associated With Familial Frontotemporal Dementia. European Journal of Neurology, 14(8), 9-10.
6. Momeni, P., Wickermaratchi, M.M., Bell, J., Arnold, R., Beer, R., Hardy, J., Revesz, T., Neal, J.W., & Morris, H.R. (2010). Familial Early Onset Frontotemporal Dementia Caused by a Novel S356T MAPT Mutation, Initially Diagnosed as Schizophrenia. Clinical Neurology and Neurosurgery, 112(10), 917-920.
7. Neary, D., Snowden, J., & Mann, D. (2005). Frontotemporal Dementia. Lancet Neurology, 4(11), 771-780.
8. Gallo, M., Tomaino, C., Puccio, G., Franqipane, F., Curcio, S.A., Bernardi, L., Geracitano, S., Anfossi, M., Mirabelli, M., Colao, R., Vasso, F., Smirne, N., Maletta, R.G., & Bruni, A.C. (2010). Novel MAPT Val75Ala Mutation and PSEN2 ArgHys in Two Siblings With Frontotemporal Dementia. Neurology Science, 31(1), 65-70.
9. Wang, X., Shen, Y., and Chen, W. (2013). Progress in Frontotemporal Dementia Research. American Journal of Alzheimer’s Disease and Other Dementias, 28(1), 15-23.
10. Perry, D., & Miller, B.L. (2013). Frontotemporal Dementia. Seminars in Neurology, 33(4), 336-341.
11. Anfossi, M., Vuono, R., Maletta, R., Virdee, K., Mirabelli, M., Colao, R., Puccio, G., Bernardi, L., Franqipane, F., Gallo, M., Geracitano, S., Tomaino, C., Curcio, S.A., Zannino, G., Lamenza, F., Duyckaerts, C., Spillantini, M.G., Losso, M.A., & Bruni, A.C. (2011). Compound Heterozygosity of 2 Novel MAPT Mutations in Frontotemporal
12. Ghidoni, R., Signorini, S., Barbiero, L., Sina, E., Cominelli, P., Villa, A., Benussi, L., & Binetti, G. (2006). The H2 MAPT Haplotype is Associated with Familial Frontotemporal Dementia. Neurobiology of Disease, 22(2), 357-362.
13. Laws, S.M., Perneczky, R., Drzezga, A., Diehl-Schmid, J., Ibach, B., Bauml, J., Eisele, T., Frostl, H., Kurz, A., & Riemenschneider, M. (2007). Association of the Tau Haplotype H2 With Age at Onset and Functional Alterations of Glucose Utilization in Frontotemporal Dementia. The American Journal of Psychiatry, 164(10), 1577-1584.
14. Stanford, P.M., Shepherd, C.E., Halliday, G.M., Brooks, W.S., Schofield, P.W., Brodaty, H., Martins, R.N., Kwok, J.B.J., & Schofield, P.R. (2003). Mutations in the Tau Gene That Cause an Increase in Three Repeat Tau and Frontotemporal Dementia. Brain: A Journal of Neurology, 126(4), 814-826.
15. Goldman, J.S., Farmer, J.M., Van Deerlin, V.M., Willhelmsen, K.C., Miller, B.L., & Grossman, M. (2004). Frontotemporal Dementia: Genetics and Genetic Counseling Dilemmas. Neurologist,10, 227-234.

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