Overview

Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity, Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia, bvFTD, PPA
Position: (GRCh38/hg38):Chr17:45962351 G>A
Position: (GRCh37/hg19):Chr17:44039717 G>A
dbSNP ID: rs63750959
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 1

Findings

This variant has been identified in several individuals diagnosed with a disorder in the frontotemporal dementia (FTD) spectrum, as well as in two individuals with Alzheimer’s disease (AD). However, it has also been reported in a healthy elderly individual, it did not segregate with disease in a family with AD,  and, although its global frequency in the gnomAD public database is low, its frequency is higher than expected for a pathogenic variant, particularly in individuals of East Asian ancestry.

R5H was first identified in an 81-year-old Japanese man who was diagnosed with probable familial FTD. He started to experience amnesia and disorientation at age 75. He exhibited no personality changes, aggressive behavior, or parkinsonism, but became nearly mute and had rigidity of the upper extremities by the time of his death at age 81. An elder brother had died at age 86 with dementia, but DNA was not available for analysis and segregation with disease could not be shown (Hayashi et al., 2002).

The variant was subsequently found in two members of a Taiwanese family (Lin et al., 2017). The proband presented at age 63 with progressive non-fluent speech and impaired memory. Several months later, he developed apraxia, bradykinesia, rigidity, and stimulus-sensitive myoclonus in his right hand. Neuropsychological examination revealed impairments in attention, verbal memory, visuospatial abilities, and executive function, as well as transcortical motor aphasia. Based on these observations and brain imaging data (See Neuropathology below), he received a clinical diagnosis of FTD (progressive primary aphasia) with features of corticobasal syndrome. A sister of the proband, reported to suffer from persistent depressive disorder, also carried the MAPT R5H variant; at the age of 60, she did not exhibit signs of cognitive or motor dysfunction. The mother of the proband, who was diagnosed with ALS at age 60, was deceased and her DNA was not available for analysis. The variant was absent in two siblings, ages 57 and 62, who were normal upon neurological examination. Six family members from the third generation, aged 24–39 years, did not carry this variant and had normal neurological exams. The variant was not found among 997 Taiwanese individuals enrolled in the Taiwan Biobank.

R5H has also been observed in patients with the behavioral variant of FTD (bvFTD). For instance, in a study of 82 Chinese patients with sporadic FTD, the R5H variant was identified in one male patient with bvFTD, in whom the age of disease onset was 75 years (Che et al., 2017). In another study of 261 Chinese Han patients with FTD, the R5H variant was observed in two females with bvFTD (Nan et al., 2024). The age of disease onset was 49 years in one and 61 years in the other, and at the time of the study they were aged 52 and 67 years, respectively.

A relationship between R5H and Alzheimer's disease (AD) has also been proposed, but the data do not strongly support a causal connection. In a large-scale screening study of individuals and families affected by late-onset AD, the variant was found in one European family; however, it did not segregate with disease (Cruchaga et al., 2012). Only one of five mutation carriers had a diagnosis of AD, and a non-carrier had the disease as well. Therefore, this rare variant is unlikely to contribute significantly to AD pathogenesis. In another study of Chinese participants with sporadic AD (n = 74) and sporadic frontotemporal lobar degeneration (n = 29), one female patient with AD was found to carry the R5H variant (Li et al., 2024). This patient first exhibited symptoms of memory loss and personality changes, including stubbornness and irritability, at the age of 71 years. This patient’s mother had suspected dementia at around 70 years of age.

The R5H variant was also detected in one out of 376 cognitively healthy subjects from the KORA-Age cohort, based in Germany. Limited information is available about this individual, but according to a description of the cohort as a whole, subjects were Caucasian and cognitively intact at age 65 or older (Schulte et al., 2015; Schulte et al., 2012).

This variant was reported in the gnomAD variant database at a global frequency of 0.000024, including 39 heterozygote carriers (gnomAD v.4.1.0, April 2024). The frequency was highest in individuals of East Asian ancestry (0.00065).

Neuropathology

A CT scan of the Japanese proband with FTD showed severe atrophy of both temporal lobes. Postmortem analysis showed neuronal loss in the frontal and temporal lobes as well as widespread tau deposits predominantly in glia. Extensive deposition of Sarkosyl-insoluble tau filaments composed of 4-repeat (4R) tau, as well as straight tubules reminiscent of progressive supranuclear palsy, were also observed (Hayashi et al., 2002).

Moreover, in the Taiwanese proband with progressive primary aphasia, asymmetric atrophy of the left frontal and temporal lobes were apparent on MRI, and SPECT showed hypometabolism in the left temporal and parietal cortices (Lin et al., 2017). In the two Chinese Han patients with bvFTD, bilateral frontal and temporal lobe atrophy was observed on MRI (Nan et al., 2024). Additionally, in the 71-year-old Chinese patient with AD, MRI revealed mild atrophy of the whole brain and of the hippocampus bilaterally (Li et al., 2024).

Biological effect

This mutation was initially reported to promote fibril formation in vitro (Hayashi et al., 2002). More recently, the propensity of the R5H variant to form inclusions was assessed using a different experimental approach: a tau seeding model with HEK293T cells (Strang et al., 2018). Contrary to the findings of Hayashi and co-workers, in R5H-expressing cells that were exposed to fibrils of wild-type K18 tau peptides, which are aggregation-prone, tau did not accumulate, indicating a lack of seeding and tau inclusion formation.

Hayashi et al. also reported that this mutation reduces tau's ability to promote microtubule assembly in vitro (Hayashi et al., 2002). More recently, microtubule binding was found to be increased in R5H versus wild-type cells in a cell-based assay using transfected HEK293T cells (Xia et al., 2019). These findings are not necessarily contradictory, as they measure different aspects of the microtubule interaction process.

In silico prediction tools yielded mixed results with some indicating it may be damaging or likely damaging—PolyPhen2 (Cruchaga et al., 2012), Mutation Taster (Che et al., 2017; Nan et al., 2024)—while others predicted it to be benign/tolerated—SIFT, Provean, PolyPhen2 (Nan et al., 2024). The variant’s PHRED-scaled CADD score was 23.6, above the commonly used threshold for predicting deleteriousness (CADD v1.7, Apr 2024).

R5H has been classified as likely pathogenic (Li et al., 2024) and pathogenic (Nan et al., 2024) based on the ACMG guidelines (Richards et al., 2015).

Research Models

An induced pluripotent stem cell line from a control male donor was engineered using CRISPR to express the R5H variant. This line is available upon request for pursuing mechanistic studies on this mutation (Karch et al., 2019; Oct 2019 news).

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References

News Citations

1. Introducing: iPSC Collection from Tauopathy Patients 23 Oct 2019

Paper Citations

1. Karch CM, Kao AW, Karydas A, Onanuga K, Martinez R, Argouarch A, Wang C, Huang C, Sohn PD, Bowles KR, Spina S, Silva MC, Marsh JA, Hsu S, Pugh DA, Ghoshal N, Norton J, Huang Y, Lee SE, Seeley WW, Theofilas P, Grinberg LT, Moreno F, McIlroy K, Boeve BF, Cairns NJ, Crary JF, Haggarty SJ, Ichida JK, Kosik KS, Miller BL, Gan L, Goate AM, Temple S, Tau Consortium Stem Cell Group. A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies. Stem Cell Reports. 2019 Nov 12;13(5):939-955. Epub 2019 Oct 17 PubMed.
2. Hayashi S, Toyoshima Y, Hasegawa M, Umeda Y, Wakabayashi K, Tokiguchi S, Iwatsubo T, Takahashi H. Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Ann Neurol. 2002 Apr;51(4):525-30. PubMed.
3. Lin HC, Lin CH, Chen PL, Cheng SJ, Chen PH. Intrafamilial phenotypic heterogeneity in a Taiwanese family with a MAPT p.R5H mutation: a case report and literature review. BMC Neurol. 2017 Sep 18;17(1):186. PubMed.
4. Che XQ, Zhao QH, Huang Y, Li X, Ren RJ, Chen SD, Wang G, Guo QH. Genetic Features of MAPT, GRN, C9orf72 and CHCHD10 Gene Mutations in Chinese Patients with Frontotemporal Dementia. Curr Alzheimer Res. 2017;14(10):1102-1108. PubMed.
5. Nan H, Kim YJ, Chu M, Li D, Li J, Jiang D, Wu Y, Ohtsuka T, Wu L. Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations. Alzheimers Res Ther. 2024 Jun 13;16(1):127. PubMed.
6. Cruchaga C, Haller G, Chakraverty S, Mayo K, Vallania FL, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, Boeve BF, Graff-Radford NR, St Jean P, Lawson M, Ehm MG, Mayeux R, Goate AM, NIA-LOAD/NCRAD Family Study Consortium. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039. Epub 2012 Feb 1 PubMed.
7. Li Y, Yang Z, Zhang Y, Liu F, Xu J, Meng Y, Xing G, Ruan X, Sun J, Zhang N. Genetic Screening of Patients with Sporadic Alzheimer's Disease and Frontotemporal Lobar Degeneration in the Chinese Population. J Alzheimers Dis. 2024;99(2):577-593. PubMed.
8. Schulte EC, Fukumori A, Mollenhauer B, Hor H, Arzberger T, Perneczky R, Kurz A, Diehl-Schmid J, Hüll M, Lichtner P, Eckstein G, Zimprich A, Haubenberger D, Pirker W, Brücke T, Bereznai B, Molnar MJ, Lorenzo-Betancor O, Pastor P, Peters A, Gieger C, Estivill X, Meitinger T, Kretzschmar HA, Trenkwalder C, Haass C, Winkelmann J. Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
9. Schulte EC, Mollenhauer B, Zimprich A, Bereznai B, Lichtner P, Haubenberger D, Pirker W, Brücke T, Molnar MJ, Peters A, Gieger C, Trenkwalder C, Winkelmann J. Variants in eukaryotic translation initiation factor 4G1 in sporadic Parkinson's disease. Neurogenetics. 2012 Aug;13(3):281-5. Epub 2012 Jun 16 PubMed.
10. Strang KH, Croft CL, Sorrentino ZA, Chakrabarty P, Golde TE, Giasson BI. Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies. J Biol Chem. 2018 Feb 16;293(7):2408-2421. Epub 2017 Dec 19 PubMed.
11. Xia Y, Sorrentino ZA, Kim JD, Strang KH, Riffe CJ, Giasson BI. Impaired tau-microtubule interactions are prevalent among pathogenic tau variants arising from missense mutations. J Biol Chem. 2019 Nov 29;294(48):18488-18503. Epub 2019 Oct 24 PubMed.
12. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Further Reading

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