Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46010405 G>A
Position: (GRCh37/hg19):Chr17:44087771 G>A
dbSNP ID: rs63750013
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift
Codon Change: G to A
Genomic Region: Intron 10

Findings

This intronic mutation was originally identified in a large kindred affected by a neurodegenerative disease termed "familial multiple-system tauopathy with presenile dementia (MSTD)." The clinical and neuropathological characteristics described, including frontotemporal atrophy and abundant tau pathology, place this disease on the frontotemporal dementia spectrum (Spillantini et al., 1998). The presenting symptoms in 17 of the 21 affected individuals in this family were consistent with the behavioral variant of frontotemporal dementia (bvFTD). Two others presented with an atypical form of progressive supranuclear palsy (PSP). One family member presented with severe postural imbalance, and another with an isolated short-term memory deficit. Memory impairment was present at onset in 15 of the affected family members (Spina et al., 2008).

This mutation was later found in a British woman with a family history of dementia accompanied by a movement disorder. She presented at age 38 with a six-month history of slurred speech, falls, and incoordination associated with involuntary movements. Cognitive decline was underway by age 38 and she rapidly developed a tremor and muscular rigidity. She died at age 44. Her mother reportedly suffered from a similar illness, and was clinically diagnosed with Huntington’s disease. She had died in her 50s but no further details are available. The proband’s sister, who was not a mutation carrier, had a diagnosis of multiple sclerosis by age 42 (Tolnay et al., 2000).

This mutation has also been described in a family of Italian heritage. The proband developed changes in speech, behavior, and social conduct around age 50 (Neumann et al., 2005). He also developed parkinsonian symptoms (e.g., tremor, rigidity, bradykinesia), and died at age 56. Family history is rather unclear. Both parents died in their mid-50s of unknown causes. One sister suffered from a similar illness and was diagnosed with either Pick’s disease or corticobasal degeneration clinically. Two brothers died in their mid-50s from heart failure. The proband’s son was also a mutation carrier, but asymptomatic at the time of the report, so segregation with disease could not be determined.

Most recently, an Italian-Polish family carrying the IVS 10 + 3 mutation was described (Wierzba-Bobrowicz et al., 2014). The reported pedigree shows a total of 25 members over four generations with six affected individuals. Of the affected individuals, DNA was available from two siblings, and both were mutation carriers, suggesting possible segregation with disease. Disease in this family presented clinically as dementia with a movement disorder compounded by a cardiovascular disorder. The two documented mutation carriers were siblings, a brother and sister. The brother developed symptoms of dementia at age 57, and died one year later. He also had muscle weakness, a cardiac pacemaker, and bulbar symptoms at the end of his life. His sister developed onset at age 59, presenting first with changes in behavior and personality. She suffered a hemorrhagic stroke at age 61 and died at age 68 with logopenic aphasia and parkinsonian symptoms. The pattern of inheritance shown in the pedigree suggests that the disease originated in Italian ancestors.

Neuropathology

In the original MSTD family, atrophy in the frontal and temporal cortices was observed as well as abundant tau pathology. Specifically, filamentous tau deposits were found in the neocortex, some in subcortical nuclei, brainstem, and spinal cord. Deposits occurred in both neurons and glia, especially within oligodendrocytes. Tau filaments had a twisted morphology and consisted primarily of isoforms containing four microtubule binding repeats (4R tau) (Spillantini et al., 1997).

Neuropathological analysis of the British proband showed widespread neuronal loss and gliosis, most severe in neocortical regions. Abundant neuronal and glial tau inclusions were observed, including paired helical filaments and twisted, ribbon-like filaments. Neurofibrillary lesions were described as argyrophilic, mature, globose or flame-shaped tangles along with extraneuronal “ghost tangles” (Tolnay et al., 2000).

Neuropathological analysis of the Italian proband showed atrophy of the frontal and temporal cortices and hippocampus. Neurofibrillary tangles were observed in the frontal and temporal cortices, as well as the hippocampus, basal ganglia, and brainstem. Tangles were primarily globoid with abundant diffuse, granular pretangles of hyperphosphorylated tau. Tau inclusions in glial cells, especially oligodendrocytes, were also widespread (Neumann et al., 2005).

Neuropathological analysis of the Italian-Polish siblings revealed similar pathology to the previously described families, including atrophy of the frontal and temporal cortices and abundant tau pathology. Tau deposits were numerous in the frontal and temporal cortices, as well as the brainstem. Tau pathology took the form of neurofibrillary tangles, neuropil threads, coiled bodies, and granular and grain-like deposits (Wierzba-Bobrowicz et al., 2014).

Biological Effect

This mutation, a G-to-A transition in the intron following exon 10, disrupts a predicted stem-loop structure and may lead to increased use of this splice site and account for the elevated levels of 4R tau isoforms in the brain (Spillantini et al., 1998).   

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References

Paper Citations

1. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7737-41. PubMed.
2. Spina S, Farlow MR, Unverzagt FW, Kareken DA, Murrell JR, Fraser G, Epperson F, Crowther RA, Spillantini MG, Goedert M, Ghetti B. The tauopathy associated with mutation +3 in intron 10 of Tau: characterization of the MSTD family. Brain. 2008 Jan;131(Pt 1):72-89. Epub 2007 Dec 7 PubMed.
3. Tolnay M, Grazia Spillantini M, Rizzini C, Eccles D, Lowe J, Ellison D. A new case of frontotemporal dementia and parkinsonism resulting from an intron 10 +3-splice site mutation in the tau gene: clinical and pathological features. Neuropathol Appl Neurobiol. 2000 Aug;26(4):368-78. PubMed.
4. Neumann M, Mittelbronn M, Simon P, Vanmassenhove B, de Silva R, Lees A, Klapp J, Meyermann R, Kretzschmar HA. A new family with frontotemporal dementia with intronic 10+3 splice site mutation in the tau gene: neuropathology and molecular effects. Neuropathol Appl Neurobiol. 2005 Aug;31(4):362-73. PubMed.
5. Wierzba-Bobrowicz T, Lewandowska E, Zaremba J, Berdyński M, Żekanowski C, Stępień T, Felczak P, Tarka S. Frontotemporal lobar degeneration with MAPT mutation in an Italian-Polish family. A case report. Folia Neuropathol. 2014;52(4):457-66. PubMed.
6. Spillantini MG, Goedert M, Crowther RA, Murrell JR, Farlow MR, Ghetti B. Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4113-8. PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database