Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP3
Clinical Phenotype Studied: Progressive Supranuclear Palsy
Position: (GRCh38/hg38):Chr17:46018644 G>A
Position: (GRCh37/hg19):Chr17:44096010 G>A
Transcript: NM_005910; ENST00000351559
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAG to AAG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

The MAPT E342K variant was first identified in a 61-year-old Chinese woman with progressive supranuclear palsy (PSP; Li et al., 2024). Her symptoms appeared at age 56, starting with recurrent falls, reduced stride, and unsteady walking, which progressively worsened. Over time, she developed additional challenges, including choking while drinking water, limited mouth opening, and excessive salivation. At the time of the report, her condition had advanced significantly, leaving her unable to walk or manage daily tasks independently, alongside issues with urinary incontinence. She also experienced cognitive decline, marked by memory impairment, hesitant speech output, irratibility, and emotional lability. Additional neurological examination revealed coordination difficulties and bilateral pyramidal signs. 

The family history in this report revealed an autosomal inheritance pattern, with a mean age of onset of 53.7 years (n=6) and a mean disease duration of 13.3 years (n=3; Li et al., 2024). Similar to the proband, the three deceased patients (all male, none of whom had genetic testing done) had walking difficulties, frequent falls, partial gaze palsy, and impaired memory. The most common initial symptom across affected individuals in this family was postural instability, while amnesia occurred as the first symptom in one case. Of note, a pedigree that appears to be the same as this one is described in another report (Nan et al., 2024).

Of the six affected individuals (including the proband), two who had genetic testing were found to be E342K carriers. Three other, unaffected family members also underwent genetic testing, one of whom was found to be a carrier; this individual—daughter of the proband—was 32 years old at the time of the report and did not exhibit any abnormalities on neurologic of neuropsychologic examination, with authors suggesting she is likely presymptomatic. The ages of the unaffected non-carriers were not reported, thus, Alzforum cannot assess co-segregation of the mutation with disease in this family.

In a separate study published the same year, another patient carrying the E342K variant was identified in a study of 290 individuals with PSP from the Mayo Clinic in Rochester, MN. This patient had the Richardson syndrome phenotype of PSP (PSP-RS; Badihian et al., 2024). He was a 62-year-old man with symptoms beginning at age 60, including tachyphemic speech, gait difficulty, fast micrographia, sleep difficulties, impulsivity, anxiety, concentration issues, and regular falls. At the time of initial evaluation, he was also experiencing severe constipation, urinary incontinence, rapid eye movement behavior disorder, and significant neck stiffness. Neurological examination revealed unsteady gait, slowing of vertical saccades, bradykinesia, axial rigidity, hypokinetic hypophonetic dysarthria, echolalia, and impaired cognition, including episodic memory deficits. One year later, he had severe axial rigidity and his cognitive function deteriorated, although urinary incontinence had resolved. With regard to family history, the father of this patient had Alzheimer’s dementia as well as slight tremors, history of falls, and trouble swallowing.

This variant was absent from the gnomAD variant database (gnomAD v4.1.0, May 2025).

Neuropathology
Neuropathological data are unavailable. However, in the 61-year-old Chinese woman, a cranial MRI revealed midbrain atrophy with a pattern consistent with PSP-RS, and an FDG-PET scan suggested hypometabolic changes in caudate nucleus, left prefrontal lobe, both temporal poles, and midbrain, also consistent with PSP-RS (Li et al., 2024). Futhermore, tau-protein deposits were identified on 18F-florzolo-tau-PET in the thalamus and brainstem bilaterally, which are similarly indiations of PSP-RS.

On brain MRI in the 62-year-old man, midbrain atrophy was similarly observed, as well as hippocampal occupancy below normal limits (Badihian et al., 2024). FDG-PET also revealed hypometabolism in the midbrain, caudate, putamen, and thalami, with a negative amyloid PET scan.

Biological Effect
The E342K variant is located in the functional microtubule-binding domain of tau. While no functional studies have been conducted to date, another MAPT variant at the same location, E342V, is associated with higher expression levels of the 4-repeat tau isoform of mRNA and negatively impacts microtubule assembly. In addition, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (27.4), suggesting a deleterious effect (CADD v.1.7, May 2025).

Based on the ACMG-AMP guidelines (Richards et al., 2015), Li and colleagues classified this variant as likely pathogenic (Li et al., 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Likely Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

Mutations Citations

1. MAPT E342V

Paper Citations

1. Li H, Li Q, Weng Q, Cui R, Yen TC, Li Y. A novel MAPT variant (E342K) as a cause of familial progressive supranuclear palsy. Front Neurol. 2024;15:1372507. Epub 2024 Apr 19 PubMed.
2. 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.
3. Badihian N, Ali F, Botha H, Savica R, Machulda MM, Clark HM, Stierwalt JA, Pham NT, Baker MC, Rademakers R, Lowe V, Whitwell JL, Josephs KA. The MAPT p.E342K and p.R406W mutations are associated with progressive supranuclear palsy with atypical features. Parkinsonism Relat Disord. 2024 Feb;119:105962. Epub 2023 Dec 17 PubMed.
4. 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

No Available Further Reading