Overview

Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity, Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia, bvFTD
Position: (GRCh38/hg38):Chr17:17:45983334 A>T
dbSNP ID: rs533610448
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to GTC
Reference Isoform: Tau Isoform PNS Tau (758 aa)
Genomic Region: Exon 4a

Findings

This variant, located in an exon present in peripheral tau isoforms but excluded from the six major isoforms expressed in the human brain, has been identified in multiple people of East Asian ancestry. A wide range of clinical phenotypes have been reported in carriers. Although D177V’s frequency in the general population is relatively low (0.000037; 60 heterozygotes; gnomAD v4.1.0, Oct 2024), it is much more prevalent in the East Asian population (0.011; 47 heterozygotes).

In a study that has identified the most D177V carriers to date, eight carriers were reported from a cohort of 1,351 Chinese Han patients with dementia collected by the Peking Union Medical College Hospital (PUMCH; Mao et al., 2021). These patients presented with varying clinical and neuroimaging phenotypes, with only one patient  considered to have a classic case of FTD. This individual had a disease onset of 51 years, characterized by aphasia, cognitive decline, and abnormal behavior. The other seven cases had a later age of onset (range 62-89 years). All seven carriers experienced cognitive decline, with three having brain alterations atypical for FTD as assessed by neuroimaging, including abundant cerebral vascular lesions indicative of small vessel disease or cerebral amyloid angiopathy. Atypical symptoms included parkinsonism in one patient and,  gait disturbance in another. Two patients had long-lasting dementia reminiscent of Alzheimer’s disease (AD), one with psychiatric symptoms. Family history of disease was present in three of the eight patients, including the patient with FTD.

The first identified case of the D177V variant was a heterozygous carrier from a study of 75 Korean patients with FTD (Kim et al., 2014). It was absent from 700 control chromosomes.

D177V was later identified in one patient with the progressive nonfluent aphasia (PNFA) variant of FTD in a study of 52 patients with FTD from mainland China (Tang et al., 2016). This carrier was a 60-year-old male who first presented with symptoms at the age of 57 years. Although his memory remained relatively intact and he was able to understand spoken language until the age of 60, at presentation he exhibited nonfluent speech characterized by a lack of content as well as difficulty correctly naming common objects. Later onset symptoms included inappropriate behaviors and apathy. None of his family members were known to have had neurodegenerative disease. The variant was absent from 300 healthy controls.

Another patient from China with the behavioral variant of FTD was also found to be heterozygous for D177V; the study population consisted of individuals with ostensibly sporadic AD (n=74) and sporadic frontotemporal lobar degeneration (n=29; Li et al., 2024). At the age of 67 years, this male patient began to exhibit behavioral disinhibition (e.g., impulsive actions, loss of manners) and apathy. This was followed by challenges in language comprehension, even though memory was relatively preserved.

Finally, a patient with AD was found to carry a heterozygous D177V variant (Chen et al., 2022). This 55-year-old woman was of Chinese Han origin and had no family history of disease.

Neuropathology

Neuropathological data are unavailable, however, neuroimaging alterations in several carriers revealed heterogeneity. In the 51-year-old patient with FTD from the PUMCH cohort, neuroimaging with MRI revealed left and frontal lobe atrophy (unilateral), while the other seven D177V-positive patients in the cohort exhibited other features on MRI, such as cerebral vascular lesions, bilateral temporal lobe atrophy, whole cortex and diffuse atrophy, and lateral ventricle enlargement (Mao et al., 2021). In the 60-year-old patient with PNFA, MRI revealed asymmetric temporal atrophy (Tang et al., 2016). And in the 67-year-old male with the behavioral variant of FTD, the left lateral temporal lobe showed mild atrophy based on MRI findings (Li et al., 2024).

Also of note, in the 55-year-old patient with AD, cerebrospinal fluid analysis demonstrated decreased Aβ42 levels, and increased levels of phosphorylated tau181 and total tau (Chen et al., 2022). Cerebrospinal fluid biomarkers of AD were also measured in one of the AD-like cases in the PUMCH cohort, but found to be absent (Mao et al., 2021).

Biological Effect

The biological effect of this variant is unknown. In silico algorithms have yielded inconsistent predictions, including possibly damaging (PolyPhen-2; Kim et al., 2014), tolerated (SIFT; Kim et al., 2014), or damaging (SIFT; Tang et al., 2016). The variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was 15.48, below the commonly used threshold of 20 for predicting deleteriousness (CADD v1.7, Oct 2024).

Based on ACMG classification guidelines, D177V has been classified as a variant of uncertain significance (Jiang et al., 2021) or as likely pathogenic (Li et al., 2024). Of note, D177V could be a risk factor for neurodegeneration (Mao et al., 2021).

Research Models

A human induced pluripotent stem cell line was generated from peripheral blood
mononuclear cells collected from the 55-year-old patient described above with sporadic Alzheimer’s disease (Chen et al., 2022).

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References

Paper Citations

1. Chen L, Zhang J, Yang X, Wang S, Ye F. Generation of human induced pluripotent stem cell lines SPPHIi003-A and SPPHIi004-A from two patients with sporadic Alzheimer's disease in Southwestern China. Stem Cell Res. 2022 Oct;64:102876. Epub 2022 Jul 28 PubMed.
2. Mao C, Dong L, Li J, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Cui L, Gao J. Phenotype Heterogeneity and Genotype Correlation of MAPT Mutations in a Chinese PUMCH Cohort. J Mol Neurosci. 2021 May;71(5):1015-1022. Epub 2020 Oct 1 PubMed.
3. Kim EJ, Kwon JC, Park KH, Park KW, Lee JH, Choi SH, Jeong JH, Kim BC, Yoon SJ, Yoon YC, Kim S, Park KC, Choi BO, Na DL, Ki CS, Kim SH. Clinical and genetic analysis of MAPT, GRN, and C9orf72 genes in Korean patients with frontotemporal dementia. Neurobiol Aging. 2014 May;35(5):1213.e13-7. Epub 2013 Dec 4 PubMed.
4. Tang M, Gu X, Wei J, Jiao B, Zhou L, Zhou Y, Weng L, Yan X, Tang B, Xu J, Shen L. Analyses MAPT, GRN, and C9orf72 mutations in Chinese patients with frontotemporal dementia. Neurobiol Aging. 2016 Oct;46:235.e11-5. Epub 2016 May 20 PubMed.
5. 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.
6. Jiang Y, Jiao B, Xiao X, Shen L. Genetics of frontotemporal dementia in China. Amyotroph Lateral Scler Frontotemporal Degener. 2021 Aug;22(5-6):321-335. Epub 2021 Feb 4 PubMed.

Further Reading

No Available Further Reading