Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr17:44087661 T>C
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Codon Change: T to C
Genomic Region: Intron 9


This intronic mutation was detected in an apparently sporadic case of frontotemporal dementia (Anfossi et al., 2011). The proband developed changes in personality and behavior at age 46, including apathy, disinhibition, depression, and aggressive behavior. Her spontaneous speech decreased, and she later became mute. She developed progressive cognitive decline, followed by extrapyramidal signs and myoclonus. She died at age 57. She did not have a family history of disease. In addition to this novel mutation in intron 9, the proband also carried a novel variant in intron 10 (IVS10+4 A>C). The extent to which these two MAPT variants contribute to disease is unknown. The proband's sister is the only other person known to carry both variants, and she was cognitively healthy at age 58 with only mild problems in attention and memory. Family members who carried only one of the two variants were cognitively healthy.


Autopsy showed severe atrophy of the frontotemporal lobes with relative sparing of the motor and visual cortices. There was atrophy of the caudate nucleus and substantia nigra. The hippocampus was severely affected by neuronal loss, with a band of dense astrocytic gliosis where neurons should have been. Abundant tau pathology was observed throughout the brain, primarily comprised of three-repeat (3R) tau isoforms, consistent with Pick's disease. Ghost tangles were noted in the cortex.

Biological Effect

When co-transfected with wild-type tau, this mutation did not significantly affect exon 10 splicing. However, when co-transfected with the IVS10+4 A>C mutation, a significant reduction in transcripts containing exon 10 was observed. The increase in transcripts lacking exon 10 resulted in an overproduction of 3R isoforms relative to four-repeat (4R) isoforms.

Last Updated: 16 Feb 2023


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Paper Citations

  1. . Compound heterozygosity of 2 novel MAPT mutations in frontotemporal dementia. Neurobiol Aging. 2011 Apr;32(4):757.e1-757.e11. PubMed.

Other Citations

  1. IVS10+4 A>C

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Compound heterozygosity of 2 novel MAPT mutations in frontotemporal dementia. Neurobiol Aging. 2011 Apr;32(4):757.e1-757.e11. PubMed.


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