Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46010303 A>T
Position: (GRCh37/hg19):Chr17:44087669 A>T
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift
Genomic Region: Intron 9

Findings

This intronic variant was identified in a Japanese man diagnosed with right temporal variant frontotemporal dementia (rtvFTD), also known as right-predominant semantic dementia (Mori et al., 2023). His early symptoms, emerging at age 52, included bizarre behaviors and difficulties with word comprehension. Two to three years later, memory loss, obsessive behaviors, and disinhibition were observed. By age 57 he suffered from agitation, indifference, disinhibition, motor symptoms, disturbed sleep, and changes in eating behaviors. Left-predominant muscle rigidity emerged later and progressed gradually.  Of note, memory impairment, including semantic memory loss, remained moderate until the proband’s death.The deceased father may have had early onset dementia, but details were unavailable.

This variant was absent from the gnomAD variant database (v2.1.1, Jan 2023).

Neuropathology
Post-mortem examination of the proband’s brain revealed severe neuronal loss and gliosis in the temporal pole, temporal gyrus, amygdala, substantia nigra, and locus coeruleus, with milder pathology in multiple other brain regions (Mori et al., 2023). Immunohistochemistry for phospho-tau revealed numerous neuronal intracytoplasmic inclusions, glial inclusions, and threads in many brain areas, with accumulation of 4-repeat (4R), but not 3R, tau particularly in the temporal lobe, amygdala, and substantia nigra. Tau filaments extracted from the brain had a ribbon-like structure with banding patterns similar to those described for other 4R tauopathies. No astrocytic plaques or tufted astrocytes were detected, nor were Aβ, Lewy body, or TDP-43 pathologies.

An MRI scan of the proband’s brain at age 59 revealed marked atrophy of the right-dominant medial temporal lobe, including the amygdala. In addition, the basal part of the right temporal lobe was severely atrophied. The hippocampus and midbrain tegmentum were only moderately affected, and the caudate, parietal lobe and cerebellum were apparently unaffected. SPECT imaging showed reduced blood flow from the right temporal pole to the mediobasal temporal lobe.

The Aβ42/Aβ40 ratio in cerebrospinal fluid was within the normal range, but phospho(181)-tau levels were slightly elevated.

Biological Effect

A cellular MAPT splicing assay revealed that this variant promotes the inclusion of exon 10, shifting production towards 4R tau (Mori et al., 2023). As noted by the authors, this biological effect is consistent with the proposal that the polypyrimidine tract in the 3’ region of intron 9 is key for regulating exon 10 inclusion during splicing (D’Souza et al., 2002).

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References

Paper Citations

1. Mori K, Shigenobu K, Beck G, Uozumi R, Satake Y, Suzuki M, Kondo S, Gotoh S, Yonenobu Y, Kawai M, Suzuki Y, Saito Y, Morii E, Hasegawa M, Mochizuki H, Murayama S, Ikeda M. A heterozygous splicing variant IVS9-7A > T in intron 9 of the MAPT gene in a patient with right-temporal variant frontotemporal dementia with atypical 4 repeat tauopathy. Acta Neuropathol Commun. 2023 Aug 10;11(1):130. PubMed.
2. D'Souza I, Schellenberg GD. tau Exon 10 expression involves a bipartite intron 10 regulatory sequence and weak 5' and 3' splice sites. J Biol Chem. 2002 Jul 19;277(29):26587-99. Epub 2002 May 8 PubMed.

Further Reading

No Available Further Reading