Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic, Other Tauopathy : Pathogenic
Clinical Phenotype: Frontotemporal Dementia, Pick's disease
Position: (GRCh38/hg38):Chr17:46024010 G>A
Position: (GRCh37/hg19):Chr17:44101376 G>A
dbSNP ID: rs63750512
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGG to AGG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 13

Findings

This mutation was first identified in one out of 30 cases of pathologically confirmed Pick's disease. At age 32 the patient began to show a decline in intellectual ability, along with forgetfulness, aggression, and a decline in personal hygiene. She deteriorated rapidly and died at age 37 (Pickering-Brown et al., 2000).

This mutation was also found in a young Australian woman with frontotemporal dementia (Bermingham et al., 2008). Her symptoms began at age 20 with a gradual decrease in speech, social withdrawal, and emotional lability. She was initially diagnosed with postpartum depression. She developed deficits in concentration and attention as well as hyperphagia, leading to excessive weight gain. As her disease progressed she required assistance with activities of daily living (e.g., showering, dressing). She developed pseudobulbar palsy, poor balance, and generalized limb spasticity. She died four years after symptom onset. Interestingly, her parents and grandparents (maternal and paternal) were all alive and well. The only other known case of dementia in the family was her maternal great-aunt, who had died of a dementing illness in her 50s. Segregation of the mutation with disease could not be assessed.

Most recently, this mutation was identified in a Chinese man with early onset frontotemporal dementia (Sun et al., 2016). His symptoms began at age 27 with changes in personality and behavior. In addition, his movements became slow and stiff. Neuropsychological testing revealed deficits in orientation, attention, calculation, recall, language, and visual construction. He later developed pyramidal features (e.g., increased muscle weakness, bilateral positive Babinski signs) and extrapyramidal features (e.g., distal tremor, rigidity, and akinesia). There were no other known cases of dementia in his family. Interestingly, the patient’s sister and father also carried the G389R mutation and were asymptomatic at age 31 and 50, respectively. The pattern of inheritance suggests autosomal dominant transmission with incomplete penetrance.

Neuropathology

At autopsy, one case showed severe atrophy of the frontal lobe with severe neuronal loss and astrocytosis with marked tissue vacuolation in the frontal cortex. The hippocampus was relatively preserved, with only mild neuronal loss in area CA1. Notably, neuritic plaques and neurofibrillary tangles were not observed (Pickering-Brown et al., 2000). Another case also had severe cortical atrophy at autopsy, predominantly of frontal and temporal lobes, with relative sparing of the parietal and occipital lobes (Bermingham et al., 2008). Autopsy results were not available in the case of the Chinese patient, but MRI showed atrophy of the frontal and temporal lobes (Sun et al., 2016).

Biological Effect

Recombinant G389R tau showed a reduced ability to promote microtubule assembly and an increased susceptibility to calpain I digestion (Pickering-Brown et al., 2000).

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References

Paper Citations

1. Pickering-Brown S, Baker M, Yen SH, Liu WK, Hasegawa M, Cairns N, Lantos PL, Rossor M, Iwatsubo T, Davies Y, Allsop D, Furlong R, Owen F, Hardy J, Mann D, Hutton M. Pick's disease is associated with mutations in the tau gene. Ann Neurol. 2000 Dec;48(6):859-67. PubMed.
2. Bermingham N, Cowie TF, Paine M, Storey E, McLean C. Frontotemporal dementia and Parkinsonism linked to chromosome 17 in a young Australian patient with the G389R Tau mutation. Neuropathol Appl Neurobiol. 2008 Jun;34(3):366-70. Epub 2007 Dec 7 PubMed.
3. Sun L, Chen K, Li X, Xiao S. Rapidly Progressive Frontotemporal Dementia Associated with MAPT Mutation G389R. J Alzheimers Dis. 2017;55(2):777-785. PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database