Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46024061 C>T
Position: (GRCh37/hg19):Chr17:44101427 C>T
dbSNP ID: rs63750424
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to TGG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 13
Research Models: 5

Findings

An R406W missense mutation in MAPT has been reported in at least 10 families worldwide, including families from Japan, the Netherlands, Sweden, Denmark, Belgium, Iran, and the United States.

The R406W mutation is considered pathogenic for frontotemporal dementia, although the clinical presentation of mutation carriers is variable and often looks like AD, especially in the early stages. Mutation carriers have been described as having clinical AD with late-onset frontal signs (Rademakers et al., 2003; Lindquist et al., 2008; Lindquist et al., 2009; Ikeuchi et al., 2008), as well as with FTD with or without parkinsonism (Reed et al., 1997; Hutton et al., 1998; Rosso et al., 2003; Passant et al., 2004; Ostojic et al., 2004; van Swieten et al., 1999) and unspecified, rapidly progressing dementia with psychosis (Saito et al., 2002). In general, the R406W mutation is associated with a later age of onset and longer disease duration than other MAPT mutations, although early onset and rapid progression also occur (e.g., Saito et al., 2002; onset at 47 years, death at 56).

Recently, people homozygous for the R406W mutation have been identified. It was found in two homozygous brothers from Iran whose symptoms of early onset FTD appeared in their 30s (see details below), and another homozygous individual also showed symptoms in his 30s, starting with agitation and personality changes. He then developed memory impairment, delusions, and social disinhibition, leading to a diagnosis of behavioral-variant FTD. He later developed parkinsonism. His symptoms appeared nearly two decades earlier than family members who were presumed heterozygotes (Ng et al., 2015).

This mutation, first reported in an American kindred from the Midwest with at least 10 affected family members over four generations (Hutton et al., 1998), is known as FTD004. The mutation was found to segregate with dementia and was transmitted in an autosomal-dominant manner. The average age at onset was 55 (range: 45 to 75 years). In this family, the clinical phenotype resembled AD, and was characterized by memory loss and personality changes. At the age of 47, the proband developed a slowly progressing memory impairment followed by a parkinsonian gait. Like other members of his family, he had a protracted disease course, surviving nearly 30 years after symptom onset. This kindred was of Danish ancestry (Reed et al., 1997).

The R406W mutation was also detected in a family from the Netherlands (Dutch4) described as having a slowly progressing dementia (van Swieten et al., 1999). The reported pedigree shows six affected individuals in three generations. Onset was insidious, starting with memory loss and personality changes. Language deficit occurred in some family members, with two individuals becoming mute eight to 10 years, respectively, after onset. The mean age at onset in this family was 59.2 ± 5.5 years, with mean duration of 12.7 ± 1.5 years.

A Belgian family (Family AD/G) with this MAPT mutation presented with a clinical phenotype consistent with Alzheimer's disease (Rademakers et al., 2003). The mutation segregated with disease in this family: It was present in four affected family members and 13 of 24 at-risk family members. In this family, memory impairment was the first symptom, later followed by behavior and speech problems. Affected individuals received diagnoses of AD, or in some cases, unspecified dementia. The average age of onset in this kindred was 58.7 ± 3.9 years (range: 54 to 65 years), with an average duration of 13.7 ± 4.7 years (range: seven to 22 years). Average age at death was 71.6 ± four years (range: 65 to 77). In this family, co-existing mutations in PSEN1, PSEN2, and exons 16 and 17 of APP were excluded.

Inherited dementia in a Swedish family is also attributed to the R406W mutation (Passant et al., 2004; Ostojic et al., 2004). The pedigree shows five confirmed cases in two generations with onset between 54 and 62 years. The clinical picture resembled both AD and FTD and was characterized by insidious onset of progressive memory decline followed by changes in personality and behavior, including disinhibition, irritability, and impulsivity. A lengthy disease duration was noted, with one family member surviving with dementia for 23 years.

A Danish family also has been identified with an autosomal-dominant inherited dementia clinically resembling AD (Lindquist et al., 2008). Several family members in a four-generation pedigree were affected. Onset started with memory impairment, with frontal symptoms occurring later in the course of the disease, which was generally of long duration. The average age of onset in the family was age 61.

Two unrelated Japanese kindreds carrying R406W have been reported (Ikeuchi et al., 2008). One family, known as P3367, had six affected individuals over three generations, with known ages of onset reported as 47 and 51. Affected individuals in this family had slowly progressive amnesia without apparent behavioral or language problems, and met NINCDS-ADRDA criteria for probable AD. The second family, P3048, also had a slowly progressing form of the disease. Two siblings with a family history of AD had symptom onset at ages 54 and 56, and were alive 17 and 13 years later, respectively.

A second American family carrying the R406W mutation was detected by whole-exome sequencing (Carney et al., 2013). Disease in this family was fairly typical of AD, starting with memory impairment, and family members met clinical criteria for AD. Four of the five affected family members also had parkinsonian symptoms that ranged in severity from co-morbid Parkinson’s disease to mild motor disturbances that emerged 17 years after cognitive symptoms. FTD features were minimal and appeared late in the disease course, if at all. Onset in this family ranged from 48 to 62 years of age. As the disease progressed, two distinct trajectories emerged, one involving rapid deterioration and the other a slow progression, underscoring clinical heterogeneity even within a family.

The R406W mutation was also described in an Iranian family with a strong family history of frontotemporal dementia (Basiri et al., 2015; Behnam et al., 2015). Notably, two members of this family, the proband and his brother, were homozygous for R406W. Both developed cognitive symptoms in their 30s. At least six other family members were heterozygous carriers. It is not clear whether the mutation segregated with disease in this large family or if the homozygous individuals had an earlier onset or more severe disease than the affected heterozygous carriers. The proband developed symptoms at age 39, starting with memory and language impairment and he developed a resting tremor and rigidity. His homozygous brother developed symptoms by age 35. At least five other siblings were affected by similar clinical phenotypes (i.e., cognitive decline, aphasia, parkinsonian symptoms), with three siblings predeceased at ages 36, 43, and 40.

Recently the spectrum of clinical presentation associated with the R406W mutation widened still further. A woman of Latin-American origin, who presented with a resting tremor consistent with Parkinson’s disease, was found to be a carrier (Hirschbichler et al., 2015). The tremor developed when she was 56 years old, and was followed soon after by forgetfulness and daytime sleepiness. Her exam also showed a postural tremor, mild dystonia, and bradykinesia, and rigidity of the right upper and lower limbs. She also developed cognitive impairment, specifically deficits in executive functioning and visuospatial processing. She was initially diagnosed with PD, although her diagnosis was later changed to FTD. Her mother was diagnosed with AD late in life, but segregation with disease could not be assessed.

Neuropathology

Neuropathological findings have been reported for several R406W carriers from multiple countries, including the United States (Reed et al., 1997; Mott et al., 2005), Holland (van Swieten et al., 1999; Rosso et al., 2000; de Silva et al., 2006), Japan (Saito et al., 2002; Ishida et al., 2015), and Denmark (Lindquist et al., 2008). In general, postmortem analysis showed bilateral frontotemporal atrophy with neuronal loss and gliosis. Also characteristic are abundant tau-positive inclusions, including widespread neurofibrillary tangles throughout the cortex and to a lesser extent in brainstem nuclei. Postmortem examination of the proband in the American kindred FTD004 showed subcortical neurofibrillary pathology similar to progressive supranuclear palsy (Reed et al., 1997). Aβ deposits have been reported in some cases (e.g., Ishida et al., 2015), but are generally sparse or absent (e.g., Reed et al., 1997; Mott et al., 2005; Saito et al., 2002).

Biological Effect

The R406W mutation alters a highly conserved residue near the C-terminus of the tau protein. Despite being located outside the microtubule-binding repeat domains, this mutation was shown to strongly reduce the ability of tau to bind microtubules (Hong et al., 1998). However, at least in cell culture, R406W has minimal impact on microtubule assembly compared to the V337M and P301L mutations, which strongly impair assembly (Hasagawa et al., 1998; Dayanandan et al., 1999). The R406W mutation does not appear to alter the ability of three-repeat (3R) or four-repeat (4R) tau to regulate microtubule dynamics (Bunker et al., 2006). 

Moreover, studies using cell and animal overexpression models (Thies and Mandelkow, 2007; Jan 2011 news), as well as patient-derived neurons (Sep 2019 news, Nakamura et al., 2019), showed that R406W tau mislocalizes to dendrites, disrupts mitochondrial transport, and causes axonal degeneration.

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References

News Citations

1. Tau’s Synaptic Hats: Regulating Activity, Disrupting Communication 18 Jan 2011
2. Mutant Tau Stiffens Axon Cytoskeleton Near Soma 20 Sep 2019

Paper Citations

1. Rademakers R, Dermaut B, Peeters K, Cruts M, Heutink P, Goate A, Van Broeckhoven C. Tau (MAPT) mutation Arg406Trp presenting clinically with Alzheimer disease does not share a common founder in Western Europe. Hum Mutat. 2003 Nov;22(5):409-11. PubMed.
2. Lindquist SG, Holm IE, Schwartz M, Law I, Stokholm J, Batbayli M, Waldemar G, Nielsen JE. Alzheimer disease-like clinical phenotype in a family with FTDP-17 caused by a MAPT R406W mutation. Eur J Neurol. 2008 Apr;15(4):377-85. Epub 2008 Feb 16 PubMed.
3. Lindquist SG, Schwartz M, Batbayli M, Waldemar G, Nielsen JE. Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort. Clin Genet. 2009 Aug;76(2):205-9. Epub 2009 Jul 29 PubMed.
4. Ikeuchi T, Kaneko H, Miyashita A, Nozaki H, Kasuga K, Tsukie T, Tsuchiya M, Imamura T, Ishizu H, Aoki K, Ishikawa A, Onodera O, Kuwano R, Nishizawa M. Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord. 2008;26(1):43-9. Epub 2008 Jun 28 PubMed.
5. Reed LA, Grabowski TJ, Schmidt ML, Morris JC, Goate A, Solodkin A, Van Hoesen GW, Schelper RL, Talbot CJ, Wragg MA, Trojanowski JQ. Autosomal dominant dementia with widespread neurofibrillary tangles. Ann Neurol. 1997 Oct;42(4):564-72. PubMed.
6. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.
7. Rosso SM, Donker Kaat L, Baks T, Joosse M, de Koning I, Pijnenburg Y, de Jong D, Dooijes D, Kamphorst W, Ravid R, Niermeijer MF, Verheij F, Kremer HP, Scheltens P, van Duijn CM, Heutink P, van Swieten JC. Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain. 2003 Sep;126(Pt 9):2016-22. Epub 2003 Jul 22 PubMed.
8. Passant U, Ostojic J, Froelich Fabre S, Gustafson L, Lannfelt L, Larsson EM, Nilsson K, Rosén I, Elfgren C. Familial presenile dementia with bitemporal atrophy. Dement Geriatr Cogn Disord. 2004;17(4):287-92. PubMed.
9. Ostojic J, Elfgren C, Passant U, Nilsson K, Gustafson L, Lannfelt L, Froelich Fabre S. The tau R406W mutation causes progressive presenile dementia with bitemporal atrophy. Dement Geriatr Cogn Disord. 2004;17(4):298-301. PubMed.
10. van Swieten JC, Stevens M, Rosso SM, Rizzu P, Joosse M, de Koning I, Kamphorst W, Ravid R, Spillantini MG, Niermeijer, Heutink P. Phenotypic variation in hereditary frontotemporal dementia with tau mutations. Ann Neurol. 1999 Oct;46(4):617-26. PubMed.
11. Saito Y, Geyer A, Sasaki R, Kuzuhara S, Nanba E, Miyasaka T, Suzuki K, Murayama S. Early-onset, rapidly progressive familial tauopathy with R406W mutation. Neurology. 2002 Mar 12;58(5):811-3. PubMed.
12. Ng AS, Sias AC, Pressman PS, Fong JC, Karydas AM, Zanto TP, De May M, Coppola G, Geschwind DH, Miller BL, Lee SE. Young-onset frontotemporal dementia in a homozygous tau R406W mutation carrier. Ann Clin Transl Neurol. 2015 Dec;2(12):1124-8. Epub 2015 Nov 12 PubMed.
13. Carney RM, Kohli MA, Kunkle BW, Naj AC, Gilbert JR, Züchner S, Pericak-Vance MA. Parkinsonism and distinct dementia patterns in a family with the MAPT R406W mutation. Alzheimers Dement. 2013 May 30; PubMed.
14. Basiri K, Ansari B, Meamar R. Frontotemporal dementia parkinsonism: Clinical findings in a large Iranian family. Adv Biomed Res. 2015;4:37. Epub 2015 Feb 11 PubMed.
15. Behnam M, Ghorbani F, Shin JH, Kim DS, Jang H, Nouri N, Sedghi M, Salehi M, Ansari B, Basiri K. Homozygous MAPT R406W mutation causing FTDP phenotype: A unique instance of a unique mutation. Gene. 2015 Oct 1;570(1):150-2. Epub 2015 Jun 15 PubMed.
16. Hirschbichler ST, Erro R, Batla A, Bhatia KP. Classic PD-like rest tremor associated with the tau p.R406W mutation. Parkinsonism Relat Disord. 2015 Aug;21(8):1002-4. Epub 2015 May 19 PubMed.
17. Mott RT, Dickson DW, Trojanowski JQ, Zhukareva V, Lee VM, Forman M, Van Deerlin V, Ervin JF, Wang DS, Schmechel DE, Hulette CM. Neuropathologic, biochemical, and molecular characterization of the frontotemporal dementias. J Neuropathol Exp Neurol. 2005 May;64(5):420-8. PubMed.
18. Rosso SM, Kamphorst W, Ravid R, van Swieten JC. Coexistent tau and amyloid pathology in hereditary frontotemporal dementia with tau mutations. Ann N Y Acad Sci. 2000;920:115-9. PubMed.
19. de Silva R, Lashley T, Strand C, Shiarli AM, Shi J, Tian J, Bailey KL, Davies P, Bigio EH, Arima K, Iseki E, Murayama S, Kretzschmar H, Neumann M, Lippa C, Halliday G, Mackenzie J, Ravid R, Dickson D, Wszolek Z, Iwatsubo T, Pickering-Brown SM, Holton J, Lees A, Revesz T, Mann DM. An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies. Acta Neuropathol. 2006 Apr;111(4):329-40. PubMed.
20. Ishida C, Kobayashi K, Kitamura T, Ujike H, Iwasa K, Yamada M. Frontotemporal dementia with parkinsonism linked to chromosome 17 with the MAPT R406W mutation presenting with a broad distribution of abundant senile plaques. Neuropathology. 2015 Feb;35(1):75-82. Epub 2014 Nov 6 PubMed.
21. Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, Geschwind DH, Bird TD, McKeel D, Goate A, Morris JC, Wilhelmsen KC, Schellenberg GD, Trojanowski JQ, Lee VM. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science. 1998 Dec 4;282(5395):1914-7. PubMed.
22. Hasegawa M, Smith MJ, Goedert M. Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett. 1998 Oct 23;437(3):207-10. PubMed.
23. Dayanandan R, Van Slegtenhorst M, Mack TG, Ko L, Yen SH, Leroy K, Brion JP, Anderton BH, Hutton M, Lovestone S. Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation. FEBS Lett. 1999 Mar 12;446(2-3):228-32. PubMed.
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Other Citations

1. V337M

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database