Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PP3, BS1
Clinical Phenotype Studied: Corticobasal Degeneration, Progressive Supranuclear Palsy, Amyotrophic Lateral Sclerosis
Position: (GRCh38/hg38):Chr17:46024073 A>C
Position: (GRCh37/hg19):Chr17:44101439 A>C
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs777148159
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAT to CAT
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 13

Findings

This mutation was identified via sequence analysis of the entire coding region of MAPT in 109 pathologically confirmed cases of corticobasal degeneration in the U.S. (Kouri et al., 2014). The clinical history of the mutation carrier begins with the development of mood and memory problems at age 63. One year later, the patient developed mild cognitive impairment and parkinsonism. The disease progressed rapidly and she developed severe memory impariment, an unsteady gait, a hand tremor, and became mute. Before her death at age 67, she was diagnosed with progressive supranuclear palsy (PSP) syndrome.

Moreover, in a U.S. study that analyzed the MAPT sequences of 4,366 individuals with amyotrophic lateral sclerosis (ALS), one affected carrier and one unaffected carrier were reported (Petrozziello et al., 2022, suppl table 1). Note that in this study, the mutation was denoted N745H based on using the tau-G (P10636-9) isoform as a reference.

This variant was reported in the gnomAD variant database at a global frequency of 0.0000089, including 13 heterozygotes, 12 of whom were of non-Finnish European ancestry (gnomAD v4.1.0, Apr 2024).

Neuropathology

Postmortem examination of the original proband's brain showed mild atrophy of the superior frontal cortex and enlargement of the lateral ventricles (Kouri et al., 2014). There was marked loss of neuromelanin in the midbrain and abundant four repeat (4R) tau-positive astrocytic plaques and numerous threads in the gray and white matter. Abundant ballooned neurons in the superior frontal cortex and significant TDP-43 pathology, especially the basal ganglia.

Biological Effect

In a brain sample, there was an increase in the 4R/3R tau mRNA ratio (Kouri et al., 2014). Recombinant tau with the N410H mutation showed a marked increase in tau filament formation compared with wild-type tau, as well as a decreased rate of microtubule assembly and a reduction in the extent of total microtubule polymerization.

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was 24.8, above the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Uncertain Significance

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

Paper Citations

1. Kouri N, Carlomagno Y, Baker M, Liesinger AM, Caselli RJ, Wszolek ZK, Petrucelli L, Boeve BF, Parisi JE, Josephs KA, Uitti RJ, Ross OA, Graff-Radford NR, DeTure MA, Dickson DW, Rademakers R. Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration. Acta Neuropathol. 2014 Feb;127(2):271-82. PubMed.
2. Petrozziello T, Amaral AC, Dujardin S, Farhan SM, Chan J, Trombetta BA, Kivisäkk P, Mills AN, Bordt EA, Kim SE, Dooley PM, Commins C, Connors TR, Oakley DH, Ghosal A, Gomez-Isla T, Hyman BT, Arnold SE, Spires-Jones T, Cudkowicz ME, Berry JD, Sadri-Vakili G. Novel genetic variants in MAPT and alterations in tau phosphorylation in amyotrophic lateral sclerosis post-mortem motor cortex and cerebrospinal fluid. Brain Pathol. 2022 Mar;32(2):e13035. Epub 2021 Nov 14 PubMed.

Further Reading

No Available Further Reading