Overview

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

Findings

This mutation was first identified in a 38-year-old patient who presented with progressive aphasia and memory disturbance (Murrell et al., 1999; Ghetti et al., 2000). Apathy followed, along with other symptoms including hyperphagia, rigidity, pyramidal signs, and ultimately a profound dementia. Death occurred at age 43. A paternal uncle had also died at age 43 with similar symptoms. Autopsy showed numerous Pick body-like inclusions, see below.

This mutation was also identified in a case of corticobasal syndrome (CBS) (Rossi et al., 2008). The patient was a 41-year-old man with progressive asymmetric signs of cortical and basal ganglia involvement consistent with CBS. MRI showed asymmetric cortical atrophy. Family history was negative for similar illnesses. The mutation was present in the patient's unaffected elderly father, suggesting possible incomplete penetrance.

Most recently, the G389R mutation was identified in a young Frenchwoman with juvenile onset frontotemporal dementia (Chaunu et al., 2013). The proband was just 17 years old when she developed changes in mood, attention, and memory. She was initially diagnosed with depression, but her condition worsened, and she developed pronounced cognitive difficulties, language impairment, and social disinhibition. She developed extrapyramidal features such as distal tremor, rigidity, and akinesia. Her eye movements were slow and she developed vertical gaze palsy. She became mute, unable to walk, and developed seizures. She died seven years after symptom onset. Her paternal uncle had died at age 37, following a rapidly progressive dementia. Likewise, her paternal grandfather had died at age 46 with a rapidly progressing dementia and was thought to have had Pick’s disease. Her great-great-uncle had died at age 42, mute and with mood disorders and a left pyramidal syndrome. The patient's paternal great-grandmother died at age 73 without dementia, despite the fact that she likely carried the mutation. The patient’s father carried the mutation but was asymptomatic at age 46 except for very mild and stable difficulties in executive functioning. Overall, the family history suggests autosomal dominant transmission of the G389R MAPT mutation, but with variable penetrance.

Neuropathology

One proband's brain showed numerous tau-positive Pick body-like inclusions in the neocortex and numerous tau-positive filamentous inclusions in axons in the frontal, temporal, and parietal lobes, and severe cerebral atrophy (Murrell et al., 1999; Ghetti et al., 2000).

Autopsy of the young French patient showed severe atrophy in the frontal and temporal lobes, including the primary motor areas. Only the occipital pole was largely spared. The ventricles were dilated and the corpus callosum very thin. The basal ganglia were normal with the exception of mild atrophy in the caudate. The substantia nigra and locus coeruleus were pale. The main lesions were neuronal loss, astrocytosis, and laminar supragranular spongiosis, especially in the most atrophic cortical areas. White matter was diffusely demyelinated. Severe neuronal loss was observed in the substantia nigra as well. Tau immunohistochemistry revealed rounded neuronal inclusions mimicking Pick bodies. Some neurons also had diffuse cytoplasmic tau staining. Affected neurons were largely restricted to cortical layers 2 and 3. Numerous tau-positive threads and coiled bodies were observed in the subcortical white matter, putamen, and brainstem. A few spherical lesions were also present in the dentate gyrus. No abnormalities were detected using antibodies directed against Aβ, TDP-43, neurofilament, FUS, or  α-synuclein (Chaunu et al., 2013).

Biological Effect

Recombinant G389R tau showed a reduced ability to promote microtubule assembly. The mutation also weakened tau binding to microtubules, and resulted in a greater aggregation propensity of tau isoforms, including those containing three-repeat (3R) domains and those with four-repeat (4R) domains.

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References

Paper Citations

1. Murrell JR, Spillantini MG, Zolo P, Guazzelli M, Smith MJ, Hasegawa M, Redi F, Crowther RA, Pietrini P, Ghetti B, Goedert M. Tau gene mutation G389R causes a tauopathy with abundant pick body-like inclusions and axonal deposits. J Neuropathol Exp Neurol. 1999 Dec;58(12):1207-26. PubMed.
2. Ghetti B, Murrell JR, Zolo P, Spillantini MG, Goedert M. Progress in hereditary tauopathies: a mutation in the Tau gene (G389R) causes a Pick disease-like syndrome. Ann N Y Acad Sci. 2000;920:52-62. PubMed.
3. Rossi G, Marelli C, Farina L, Laurà M, Maria Basile A, Ciano C, Tagliavini F, Pareyson D. The G389R mutation in the MAPT gene presenting as sporadic corticobasal syndrome. Mov Disord. 2008 Apr 30;23(6):892-5. PubMed.
4. Chaunu MP, Deramecourt V, Buée-Scherrer V, Le Ber I, Brice A, Ehrle N, El Hachimi K, Pluot M, Maurage CA, Bakchine S, Buée L. Juvenile Frontotemporal Dementia with Parkinsonism Associated with Tau Mutation G389R. J Alzheimers Dis. 2013 Jan 1;37(4):769-76. PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database