Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr17:44087782 C>T
dbSNP ID: rs63750972
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift
Codon Change: C to T
Genomic Region: Intron 10


A disorder called disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) was originally described in a large kindred with familial adult-onset behavioral disturbance, followed by frontal-lobe dementia, parkinsonism, and amyotrophy. There were at least 13 affected individuals with an average age of onset of 45. The full clinical picture typically developed over five to 10 years, beginning with personality changes, especially disinhibition, progressing to emotional blunting and withdrawal. The average disease duration was 13 years (Lynch et al., 1994). The causative mutation was later found to be IVS10 + 14 C>T (Hutton et al., 1998).

Later, this mutation was identified in two Japanese sisters affected by a tauopathy syndrome clinically characterized by parkinsonism, depression, weight loss, and hypoventilation (Omoto et al., 2012). Although this particular constellation of symptoms is consistent with Perry syndrome, a degenerative brain disease linked to mutations in the dynactin gene, no dynactin mutations were found. Rather, the sisters were found to carry the 10+14 intronic mutation in MAPT. Clinically, the proband developed symptoms at age 44, starting as clumsiness, weight loss, apathy, and tremor in the upper limbs. Motor symptoms progressed to include bradykinesia and muscle rigidity. She was also affected by central hypoventilation, leading to her death from sudden apnea within two years of symptom onset. Limited information was reported about the proband’s sister. She is described as presenting with delusions and hallucinations at age 19. By age 43 she had developed spasticity. Their mother had developed parkinsonism at age 48 and died at age 54.

This mutation was described in a second Japanese family in which three sisters were affected by a dementia syndrome with varying clinical presentations (Kotoku et al., 2012). One sister reportedly suffered from FTD with parkinsonism while another had FTD without parkinsonism. Disease in the third sister started with memory problems at age 46. Only later did she develop changes in personality and behavior along with parkinsonism.


Autopsy in the initial kindred showed atrophy and spongiform changes in the frontotemporal cortex, along with neuronal loss and gliosis in the substantia nigra and amygdala (Lynch et al., 1994; Sima et al., 1996). 

Autopsy of the Japanese proband showed neuropathology consistent with a 4R tauopathy, such as progressive supranuclear palsy (Omoto et al., 2012). Severe neuronal loss and gliosis were observed in the globus pallidus, subthalamic nucleus, substantia nigra, locus ceruleus, and brainstem. Abundant tau pathology in the form of globose neurofibrillary tangles was noted, along with neuropil threads and tau-positive inclusions in oligodendrocytes. Tau deposits primarily consisted of 4R tau. TDP-43 staining was negative. Severe gliosis and deposition of 4R tau was noted in the medulla.

Biological Effect

This mutation occurs at a splice site and destabilizes a stem-loop structure that regulates the alternative splicing of exon 10. This causes more frequent inclusion of exon 10 in tau mRNA transcripts and leads to an increase in the proportion of four-repeat (4R) tau isoforms (Hutton et al., 1998).

Last Updated: 16 Feb 2023


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Paper Citations

  1. . Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex. Neurology. 1994 Oct;44(10):1878-84. PubMed.
  2. . Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.
  3. . Autosomal dominant tauopathy with parkinsonism and central hypoventilation. Neurology. 2012 Feb 22; PubMed.
  4. . FTDP-17 presenting amnestic MCI as an initial symptom: case report. Rinsho Shinkeigaku. 2012;52(2):73-8. PubMed.
  5. . The neuropathology of chromosome 17-linked dementia. Ann Neurol. 1996 Jun;39(6):734-43. PubMed.

Further Reading


  1. . Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13103-7. PubMed.
  2. . The genetic and pathological classification of familial frontotemporal dementia. Arch Neurol. 2001 Nov;58(11):1813-6. PubMed.
  3. . Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations. Neuroimage. 2010 Nov 15;53(3):1070-6. Epub 2010 Jan 4 PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database
  2. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. . Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.


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