Mutations

MAPT R406W

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Genome Build: 105
Position: Chr17:44101427 C>T
dbSNP ID: rs63750424
Coding/Non-Coding: Coding
Genomic Region: Exon 13
Mutation Type: Point, Missense
Codon Change: CGG to TGG
Research Models: 5

Findings

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

This mutation segregates with a variable form of dementia, often clinically resembling AD, although significant clinical heterogeneity has been described. Specifically, this mutation has been associated with an AD phenotype with late onset of frontal signs (Rademakers et al., 2003; Lindquist et al., 2008; Lindquist et al., 2009; Ikeuchi et al., 2008), as well as frontotemporal dementia 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 rapidly progressing dementia with psychosis (Saito et al., 2002). In general, the R406W mutation is associated with a later age at onset and longer disease duration than other MAPT mutations, although early onset and rapid progression also have been reported (e.g., Saito et al., 2002; onset: 47 years; death: 56 years). Recently, this mutation was reported in the homozygous state in two affected brothers from Iran, with onset in their 30s (Basiri et al., 2015).

This mutation, first reported in an American kindred from the Midwest that had 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 10 years 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: 7 to 22 years). Average age at death was 71.6 ± 4.0 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 has also 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. Mutations in PSEN1 and PSEN2 (exons 3-12) were excluded, along with mutations in APP (exons 16-17).

Two unrelated Japanese kindreds carrying R406W also 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 years, and were alive 17 and 13 years later, respectively.

Recently, 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.

Most recently, the R406W mutation was described in an Iranian family with a strong family history of frontotemporal dementia (Basiri 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 affected heterozygous carriers. The proband developed insidious onset at age 39, starting with memory and language impairment. His speech output decreased and he developed parkinsonian signs such as resting tremor and rigidity. His homozygous brother developed onset 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.

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, and De Silva et al., 2006), Japan (Saito et al., 2002; Ishida et al., 2014), 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., 2014), but are generally sparse or absent (e.g., Reed et al., 1997; Mott et al., 2005; Saito et al., 2002).

Biological Effect

This mutation alters a highly conserved residue near the C-terminus of the tau protein. Despite being located outside the microtubule-binding repeats, this mutation was shown to strongly reduce microtubule binding capacity (Hong et al., 1998). Tau isoforms with this mutation also exhibit a reduced ability to promote microtubule assembly/extension, suggesting partial loss of function (Hasagawa et al., 1998; Dayanandan et al., 1999); however, other studies have shown that the R406W mutation does not alter the ability of three-repeat (3R) or four-repeat (4R) tau to regulate microtubule dynamics (e.g., Bunker et al., 2006).

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References

Paper Citations

  1. . 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. . 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. . 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. . 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. . Autosomal dominant dementia with widespread neurofibrillary tangles. Ann Neurol. 1997 Oct;42(4):564-72. PubMed.
  6. . 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. . 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. . Familial presenile dementia with bitemporal atrophy. Dement Geriatr Cogn Disord. 2004;17(4):287-92. PubMed.
  9. . The tau R406W mutation causes progressive presenile dementia with bitemporal atrophy. Dement Geriatr Cogn Disord. 2004;17(4):298-301. PubMed.
  10. . Phenotypic variation in hereditary frontotemporal dementia with tau mutations. Ann Neurol. 1999 Oct;46(4):617-26. PubMed.
  11. . Early-onset, rapidly progressive familial tauopathy with R406W mutation. Neurology. 2002 Mar 12;58(5):811-3. PubMed.
  12. . Frontotemporal dementia parkinsonism: Clinical findings in a large Iranian family. Adv Biomed Res. 2015;4:37. Epub 2015 Feb 11 PubMed.
  13. . Parkinsonism and distinct dementia patterns in a family with the MAPT R406W mutation. Alzheimers Dement. 2013 May 30; PubMed.
  14. . Neuropathologic, biochemical, and molecular characterization of the frontotemporal dementias. J Neuropathol Exp Neurol. 2005 May;64(5):420-8. PubMed.
  15. . Coexistent tau and amyloid pathology in hereditary frontotemporal dementia with tau mutations. Ann N Y Acad Sci. 2000;920:115-9. PubMed.
  16. . 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.
  17. . 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.
  18. . Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science. 1998 Dec 4;282(5395):1914-7. PubMed.
  19. . Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett. 1998 Oct 23;437(3):207-10. PubMed.
  20. . 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.
  21. . FTDP-17 mutations compromise the ability of tau to regulate microtubule dynamics in cells. J Biol Chem. 2006 Apr 28;281(17):11856-63. PubMed.

Further Reading

Papers

  1. . Molecular analysis of mutant and wild-type tau deposited in the brain affected by the FTDP-17 R406W mutation. Am J Pathol. 2001 Feb;158(2):373-9. PubMed.
  2. . 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.
  3. . High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet. 1999 Feb;64(2):414-21. PubMed.
  4. . Imaging findings of familial dementia with a tau R406W mutation. Acta Neurol Belg. 2011 Dec;111(4):374-5. PubMed.
  5. . The frontotemporal dementia mutation R406W blocks tau's interaction with the membrane in an annexin A2-dependent manner. J Cell Biol. 2011 Feb 21;192(4):647-61. PubMed.
  6. . Dementia mimicking Alzheimer's disease Owing to a tau mutation: CSF and PET findings. Alzheimer Dis Assoc Disord. 2010 Jul-Sep;24(3):303-7. PubMed.
  7. . Evidence for a Common Founder and Clinical Characteristics of Japanese Families with the MAPT R406W Mutation. Dement Geriatr Cogn Dis Extra. 2011 Jan;1(1):267-75. Epub 2011 Sep 20 PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . 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.

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