Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP3
Clinical Phenotype Studied: Corticobasal Degeneration, Progressive Supranuclear Palsy
Position: (GRCh38/hg38):Chr17:46010338 T>G
Position: (GRCh37/hg19):Chr17:44087704 T>G
Transcript: NM_005910; ENST00000351559
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to CGT
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This very rare mutation was originally identified in a Caucasian woman from southern England. The family had an autosomal-dominant progressive supranuclear palsy syndrome characterized by early falls and a behavioral syndrome. Symptoms typically became apparent in the 40s, with an average disease duration of four to seven years (Rohrer et al., 2011). The clinical phenotype of another carrier of the mutation, one of the proband's sons, was consistent with the family's syndrome (Cullinane et al., 2023). 

This variant is absent from the gnomAD public variant database (gnomAD v4.1.1, Apr 2024).

Neuropathology
Neuropathology typical of corticobasal degeneration was observed in post-mortem brain tissue from the proband's son (Cullinane et al., 2023). Pathology included severe atrophy of the subthalamic nucleus and substantia nigra, with mild atrophy of the dentate nucleus. Phosphorylated tau (AT8 antibody) was prominent in glia and neurons across the putamen, globus pallidus, and subthalamic nucleus. In the latter, densely packed threads and globose tangles were observed. Hippocampal neuropathology varied across regions. In the frontal cortex, astrocytic plaques, pre-tangles, tangles, and threads were identified. No signs of neuropathology involving α-synuclein, Aβ or TDP43 were observed. 

Prior to death, a brain MRI scan of this carrier revealed midbrain atrophy, with very mild frontal and parietal atrophy. 

Biological Effect
In an assay using human embryonic kidney (HEK293T) cells, this mutation resulted in decreased binding of tau to microtubules (Xia et al., 2019). Although a neighboring variant, L284L, increases tau isoforms containing four microtubule-binding repeats (4R) by facilitating the inclusion of exon 10, L284R did not affect splicing in a cell-based minigene splicing assay (Tubeuf et al., 2020). In addition, L284R tau does not appear to induce aggregation as observed in cultured cells, even in the presence of K18, a tau fragment that seeds aggregation (Xia et al., 2019).

This variant's PHRED-scaled CADD score (31), which integrates diverse information in silico, was well above the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : 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 L284L

Paper Citations

1. Rohrer JD, Paviour D, Vandrovcova J, Hodges J, de Silva R, Rossor MN. Novel L284R MAPT mutation in a family with an autosomal dominant progressive supranuclear palsy syndrome. Neurodegener Dis. 2011;8(3):149-52. Epub 2010 Sep 14 PubMed.
2. Cullinane PW, Fumi R, Theilmann Jensen M, Jabbari E, Warner TT, Revesz T, Morris HR, Rohrer JD, Jaunmuktane Z. MAPT-Associated Familial Progressive Supranuclear Palsy with Typical Corticobasal Degeneration Neuropathology: A Clinicopathological Report. Mov Disord Clin Pract. 2023 Apr;10(4):691-694. Epub 2023 Mar 11 PubMed.
3. 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.
4. Tubeuf H, Charbonnier C, Soukarieh O, Blavier A, Lefebvre A, Dauchel H, Frebourg T, Gaildrat P, Martins A. Large-scale comparative evaluation of user-friendly tools for predicting variant-induced alterations of splicing regulatory elements. Hum Mutat. 2020 Oct;41(10):1811-1829. Epub 2020 Aug 16 PubMed.

Further Reading

No Available Further Reading