Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46010415 A>G
Position: (GRCh37/hg19):Chr17:44087781 A>G
dbSNP ID: rs63750308
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift
Codon Change: A to G
Genomic Region: Intron 10

Findings

This mutation was originally described in a British kindred known as MAN19. The three affected family members experienced changes in behavior and social conduct consistent with frontotemporal dementia (Hutton et al., 1998). Apathy and inertia were prominent in one mutation carrier who developed symptoms at age 65 and had a disease duration of only five years. A similar pattern was reported in his father and sister (Pickering-Brown et al., 2002).

Neuropathology

MRI showed cerebral atrophy that was most prominent in the temporal lobes. SPECT showed frontal and temporal dysfunction, particularly on the left side. Postmortem examination showed severe "knife‐edge" atrophy in the frontal and temporal lobes. Frequent neurofibrillary and glial tangles were observed, and were more moderate in the brainstem. Occasional ballooned neurons were also observed, along with damage to the substantia nigra (Pickering-Brown et al., 2002).

Biological Effect

This intronic mutation is thought to disrupt a splice site by destabilizing a stem-loop structure that regulates the alternative splicing of exon 10 (Hutton et al., 1998).

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References

Paper Citations

1. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. 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.
2. Pickering-Brown SM, Richardson AM, Snowden JS, McDonagh AM, Burns A, Braude W, Baker M, Liu WK, Yen SH, Hardy J, Hutton M, Davies Y, Allsop D, Craufurd D, Neary D, Mann DM. Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene. Brain. 2002 Apr;125(Pt 4):732-51. PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database