Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic, Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP1, PP3
Clinical Phenotype Studied: Alzheimer's Disease, bvFTD, Parkinsonism
Position: (GRCh38/hg38):Chr17:46010416 C>T
Position: (GRCh37/hg19):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
Research Models: 2

Findings

This variant was originally identified in an Irish-American family with a hereditary disorder in the frontotemporal dementia (FTD) spectrum. The disorder was called disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) and was characterized by 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, Clark et al., 1998). Of note, four affected carriers and 16 unaffected non-carriers that were past the family's mean age at onset, indicated co-segregation with disease (Clark et al., 1998). Although the ages of the non-carriers were not reported, at least one non-carrier was in a generation above that of several affected carriers. 

IVS10+14 C>T was subsequently reported in a family from the U.K. with a mean age at onset of 45 years and a clinical phenotype described as frontal syndrome with dyspraxia (Morris et al., 2001).

Later, the 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.

This variant was also reported in an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature (Moore et al., 2020, suppl tables 5-6). Two families, including 19 presumed carriers, were reported.  Data included both confirmed mutation carriers and family members who were assumed to be carriers based on their clinical phenotype. Fourteen of the affected individuals were diagnosed with the behavioral variant of FTD (bvFTD), one with Alzheimer’s disease, and four with dementia not otherwise specified. Mean age at onset was 44.6 years and mean age at death 55.6 years. The families reported in this study may be the same as one or two of the families described above.

This variant was absent from the gnomAD public variant database (gnomAD v4.1.1, Apr 2024).

Neuropathology

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). In addition, analysis of the insoluble fractions of brain homogenates suggested tau isoforms containing four microtubule binding repeats (4R) were present in tau aggregates (Clark et al., 1998). 

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

Consistent with the 4R tau pathology observed in carriers, increased incorporation of exon 10 was observed in mutant tau RNA constructs compared to wildtype constructs, as assessed by exon-trapping experiments in vitro (Hutton et al., 1998), Moreover, 4R isoforms are increased substantially in cultured cells expressing mutant constructs (Jiang et al., 2000, Lisowiec et al., 2015, Chen et al., 2019), as well as in neurons derived from induced pluripotent stem cells (iPSCs) from a mutation carrier (Imamura et al., 2016).

IVS10+14 C>T resides in an inhibitory stem-loop structure formed at the E10/I10 junction that blocks access of U1 snRNA to the 5′ splice site (Grover et al., 1999, Jiang et al., 2000). The thermodynamic stability of this stem-loop is greatly reduced by this mutation, as indicated by RNA gel migration patterns (Grover et al., 1999), susceptibility of mutant tau constructs to RNAse cleavage (Grover et al., 1999, Jiang et al., 2000), mutant RNA melting temperature, and computer modeling (Lisowiec et al., 2015, Chen et al., 2019). This instability results in increased recognition by U1 snRNP, and therefore increased exon 10 splicing.

The destabilization also appears to affect the binding of additional splicing factors, including the polypyrimidine tract binding protein associated splicing factor (PSF), and DEAD/H box polypeptide 5 (DDX5), a.k.a RNA helicase p68 (p68). PSF is a splicing regulator expressed at high levels in the hippocampus and the cortex. It stabilizes the 5’ splice site stem-loop structure and prevents it from adopting a more open conformation that facilitates U1snRNP binding to the 5′ splice site (Ray et al., 2011). The mutation’s destabilization of the structure is thought to decrease PSF binding. p68 also requires a stable stem-loop structure for binding which IVS10+14 C>T disrupts, but unlike PSF, p68 is a structure destabilizer (Kar et al., 2011). Thus, in the presence of the mutation, p68 does not enhance exon 10 inclusion further.

A study using neurons derived from induced pluripotent stem cells (iPSCs) from a carrier revealed additional effects associated with this mutation (Imamura et al., 2016). An increase in misfolded tau was detected in these cells by the TOC1 antibody which recognizes oligomeric tau aggregates. Moreover, the authors reported elevated calcium responses to electrical stimulation.

This variant's PHRED-scaled CADD score (22.1), which integrates diverse information in silico, was above the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Research Models

Induced pluripotent stem cells (iPSC) from a carrier of this mutation have been generated, as well as an isogenic iPSC line carrying the corrected mutation (Imamura et al., 2016). Both lines have been differentiated into neurons.

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References

Paper Citations

1. Imamura K, Sahara N, Kanaan NM, Tsukita K, Kondo T, Kutoku Y, Ohsawa Y, Sunada Y, Kawakami K, Hotta A, Yawata S, Watanabe D, Hasegawa M, Trojanowski JQ, Lee VM, Suhara T, Higuchi M, Inoue H. Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons. Sci Rep. 2016 Oct 10;6:34904. PubMed.
2. Lynch T, Sano M, Marder KS, Bell KL, Foster NL, Defendini RF, Sima AA, Keohane C, Nygaard TG, Fahn S. Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex. Neurology. 1994 Oct;44(10):1878-84. PubMed.
3. Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, Li D, Payami H, Awert F, Markopoulou K, Andreadis A, D'Souza I, Lee VM, Reed L, Trojanowski JQ, Zhukareva V, Bird T, Schellenberg G, Wilhelmsen KC. 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.
4. Morris HR, Khan MN, Janssen JC, Brown JM, Perez-Tur J, Baker M, Ozansoy M, Hardy J, Hutton M, Wood NW, Lees AJ, Revesz T, Lantos P, Rossor MN. The genetic and pathological classification of familial frontotemporal dementia. Arch Neurol. 2001 Nov;58(11):1813-6. PubMed.
5. Omoto M, Suzuki S, Ikeuchi T, Ishihara T, Kobayashi T, Tsuboi Y, Ogasawara J, Koga M, Kawai M, Iwaki T, Kanda T. Autosomal dominant tauopathy with parkinsonism and central hypoventilation. Neurology. 2012 Feb 22; PubMed.
6. Kutoku Y, Miyazaki Y, Yamashita Y, Kuwano R, Murakami T, Sunada Y. FTDP-17 presenting amnestic MCI as an initial symptom: case report. Rinsho Shinkeigaku. 2012;52(2):73-8. PubMed.
7. Sima AA, Defendini R, Keohane C, D'Amato C, Foster NL, Parchi P, Gambetti P, Lynch T, Wilhelmsen KC. The neuropathology of chromosome 17-linked dementia. Ann Neurol. 1996 Jun;39(6):734-43. PubMed.
8. 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.
9. Jiang Z, Cote J, Kwon JM, Goate AM, Wu JY. Aberrant splicing of tau pre-mRNA caused by intronic mutations associated with the inherited dementia frontotemporal dementia with parkinsonism linked to chromosome 17. Mol Cell Biol. 2000 Jun;20(11):4036-48. PubMed.
10. Lisowiec J, Magner D, Kierzek E, Lenartowicz E, Kierzek R. Structural determinants for alternative splicing regulation of the MAPT pre-mRNA. RNA Biol. 2015;12(3):330-42. PubMed.
11. Chen JL, Moss WN, Spencer A, Zhang P, Childs-Disney JL, Disney MD. The RNA encoding the microtubule-associated protein tau has extensive structure that affects its biology. PLoS One. 2019;14(7):e0219210. Epub 2019 Jul 10 PubMed.
12. Grover A, Houlden H, Baker M, Adamson J, Lewis J, Prihar G, Pickering-Brown S, Duff K, Hutton M. 5' splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10. J Biol Chem. 1999 May 21;274(21):15134-43. PubMed.
13. Ray P, Kar A, Fushimi K, Havlioglu N, Chen X, Wu JY. PSF suppresses tau exon 10 inclusion by interacting with a stem-loop structure downstream of exon 10. J Mol Neurosci. 2011 Nov;45(3):453-66. Epub 2011 Sep 1 PubMed.
14. Kar A, Fushimi K, Zhou X, Ray P, Shi C, Chen X, Liu Z, Chen S, Wu JY. RNA helicase p68 (DDX5) regulates tau exon 10 splicing by modulating a stem-loop structure at the 5' splice site. Mol Cell Biol. 2011 May;31(9):1812-21. Epub 2011 Feb 22 PubMed.

Other Citations

1. Hutton et al., 1998

Further Reading