Abstract
Mutations in microtubule‐associated protein tau gene (MAPT) cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17). Here, we describe a patient with FTDP‐17 and a novel missense mutation in exon 13 of MAPT, p.E372G. We compare clinicopathologic features of this patient to two previously unreported patients with another exon 13 mutation, p.G389R. The patient with the p.E372G mutation was a 40‐year‐old man with behavioral variant frontotemporal dementia (bvFTD), who subsequently developed agrammatic speech and parkinsonism. One of the FTDP‐17 patients with p.G389R mutation presented at age 24 with agrammatic variant of primary progressive aphasia, and subsequently behavioral dysfunction. The other presented at age 53 with bvFTD, followed by agrammatic speech and corticobasal syndrome. Neuropathologic features of FTDP‐17 due to p.E372G were similar to those of p.G389R, including tau‐immunoreactive Pick body‐like neuronal inclusions and swollen, tapering thread‐like processes in white matter immunoreactive for 3‐repeat and 4‐repeat tau. Biochemical analysis of insoluble tau showed similar isoform compositions in p.E372G and p.G389R. Functional studies of the p.E372G mutation showed marked increase in tau filament formation and its reduced ability to promote microtubule assembly. Together these findings indicate that p.E372G is a pathogenic MAPT mutation that causes FTDP‐17 similar to p.G389R.
Keywords: frontotemporal dementia, FTDP‐17, MAPT mutations, Pick's disease, primary progressive aphasia
Introduction
Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17) is a group of neurodegenerative tauopathies caused by mutations in the microtubule‐associated protein tau (MAPT) gene 14, 24, 30. Tau stabilizes microtubules and is important for neuronal integrity and axonal transport. Both silent and missense mutations in MAPT can affect tau mRNA splicing, altering the ratio of 3‐repeat (3R) and 4‐repeat (4R) tau. They can also disrupt the affinity of tau to bind and stabilize microtubules and promote pathologic assembly of abnormal tau filaments, ultimately leading to neuronal degeneration 7. Most tau mutations are located in exons 9 through 12, comprising the microtubule‐binding domain of tau, and most appear to modestly reduce microtubule assembly and promote abnormal tau aggregation 29.
FTDP‐17 has been reported in about 150 families 9, while the vast majority of tauopathies are sporadic conditions. Their clinicopathological phenotypes depend on tau isoform composition, relative disposition of abnormal tau in neurons and glia, as well as different anatomic distribution of tau pathology and neuronal loss. Most studies suggest that 3R tau preferentially deposits in neurons, whereas 4R tau deposits in both neurons and glia 18. Pick's disease and some cases of FTDP‐17 (eg, p.Q336H 31) are classified as 3R tauopathies, while progressive supranuclear palsy, corticobasal degeneration (CBD), globular glial tauopathy, argyrophilic grain disease, and some forms of FTDP‐17 (eg, p.N410H 17) are 4R tauopathies. Primary age‐related tauopathy, chronic traumatic encephalopathy, and some cases of FTDP‐17 (eg, p.G389R 21) are classified as 3R + 4R tauopathies due to accumulation of both 3R and 4R in pathologic lesions 18.
In the process of screening autopsy‐confirmed neurodegenerative tauopathies from the Mayo Clinic brain bank for neurodegenerative disorders, we discovered several mutations in the last coding exon of MAPT, exon 13, including p.N410H 17 and p.E372G described in this report. We compare and contrast clinicopathologic features of p.E372G to two previously unreported and unrelated patients with another exon 13 mutation, p.G389R, and demonstrate that they have similar clinicopathologic phenotypes 2, 4, 8, 16, 21, 23.
Materials and Methods
Subjects and samples
The p.E372G patient was referred to the State of Florida Alzheimer Disease Initiative brain bank at Mayo Clinic. The two p.G389R patients were enrolled in the Mayo Clinic Alzheimer's Disease Research Center. Autopsies were performed after approval by the next‐of‐kin. Control DNA samples were obtained from patients seen at the Mayo Clinic Florida after informed consent and according to protocols approved by the Mayo Clinic Institutional Review Board. They were considered by the neurologist to be cognitively normal at the time of blood draw.
Fixed tissue sampling and neuropathologic assessment
Primary and association cortices, basal ganglia, diencephalon, brainstem, and cerebellum were evaluated with tau immunohistochemistry (IHC). Thioflavin‐S fluorescent microscopy was used to assess Alzheimer‐type pathology; hematoxylin and eosin stained sections were used to evaluate neuronal loss and gliosis; and Luxol fast blue (LFB) was used to assess white matter changes. For tau immunohistochemistry, sections were pretreated with steam in deionized water for 30 min and processed using a DAKO Autostainer (Universal Staining System, Carpinteria, CA, USA) using 3,3′‐diaminobenzidine (DAB) as the chromogen. A phospho‐tau antibody (CP13, mouse IgG1, 1:1000, gift from Dr Peter Davies, Feinstein Institute for Medical Research, North Shore/Long Island Jewish Health Care System), 3R tau antibody (RD3, 1:5000, Millipore, Temecula, CA, USA), and 4R tau antibody (RD4, 1:5000, Millipore, Temecula, CA, USA). Alzheimer's disease tissue was used as a positive control for RD3 and RD4. Additional antibodies used include a monoclonal phospho‐TDP‐43 antibody (ps409/410, 1:5000, Cosmobio Co., Tokyo, Japan), IBA‐1 (1:3000, Wako Laboratory Chemicals, Richmond, VA, USA), and β‐amyloid antibody (clone 6F/3D; Novocastra Vector Labs, Burlingame, CA, USA). After immunostaining, sections were briefly counterstained with hematoxylin. Gallyas silver stain was used to assess argyrophilic properties of tau inclusions. Formalin‐fixed frontal white matter samples were processed for electron microscopy (EM), as previously reported 32.
Genetic analysis
DNA was extracted from frozen cerebellar tissue with Gentra Puregene kit (Qiagen, Valencia, CA, USA). Polymerase chain reactions (PCR) of approximately 300 bp fragments were performed using primer sets designed to flank all MAPT exons, except exons 4a and 8, which are not expressed in the central nervous system, as previously described 32. MAPT H1/H2 haplotype was defined by the single‐nucleotide polymorphism rs1052553 in MAPT exon 9.
Biochemical and tau functional studies
Homogenates and sarkosyl‐insoluble fractions were prepared from 100 mg samples of frontal and temporal cortex that were obtained from frozen brain tissue of the p.E372G case, the p.G389R case 2, and a p.P301L case as previously described 17. The pellets containing insoluble tau proteins were re‐suspended in 100 μL of TBS pH 7.6 and used for EM and Western blotting.
Recombinant tau was expressed and purified as previously described 17. Wild type (WT) tau and p.E372G mutant tau, each in 4R0N cDNAs, were cloned into pET30a and expressed in competent BL21 (DE3) cells. Microtubule assembly and tau filament formation were assessed with mutant 4R p.E372G tau and compared with WT tau as previously described 17. Reactions were run in quadruplicate and statistical analyses were performed using Student's t test. Tau filament formation was assessed by inducing aggregation of recombinant WT or p.E372G tau with polyglycosaminoglycan and visualizing filaments by EM as previously described 17. Tau filament formation was further analyzed with thioflavin‐S fluorescence to independently confirm aggregation properties (data not shown).
Results
Molecular genetic examination
Sequence analysis of genomic DNA identified a novel mutation: c.1115 A > G (ENST00000351559; NM_005910.5), resulting in a p.E372G (glutamine to glycine) change at a highly conserved amino acid residue (Figure 1). The mutation was further excluded from 1224 healthy controls, and was not present in Phase 3 1000 Genomes (based on Ensembl v83 GRCh37); (http://www.ensembl.org/) 1, 5, dbSNP (146; (https://www.ncbi.nlm.nih.gov/SNP/), or the Exome Variant Server (http://evs.gs.washington.edu/EVS/) databases. The patient with the p.E372G mutation was homozygous for the H1 MAPT haplotype. Both mutations, p.E372G and p.G389R, in three patients from this study were identified by the neurogenetics laboratory at the Mayo Clinic Florida.
Figure 1.
Novel MAPT p.E372G mutation identified in this study. Sequence analysis of genomic DNA identified a novel mutation c.1115 A>G (ENST00000351559; NM_005910.5). Chromatograms of the mutant and wild‐type sequence of MAPT exon 13 mutation, p.E372G, and the evolutionary conservation of MAPT is shown across various species.
Clinical examination
MAPT p.E372G patient
The p.E372G patient was a white, right‐handed man with 16‐years of education who presented at 40 years of age with changes in personality, behavior and depressive mood suggestive of behavioral variant of frontotemporal dementia (bvFTD). With time there were also cognitive deficits affecting judgment, insight, and long‐term memory. Additionally, the patient developed agrammatic speech with decreased speech output and phonemic paraphasias. On examination at age 50 he had mild bradykinesia, bilateral reduced arm swing, mild neck rigidity, and facilitatory paratonia. He had symmetrically increased deep tendon reflexes, but no other long tract signs. On brain magnetic resonance imaging (MRI), frontal and temporal atrophy was observed. 18F‐fluorodeoxyglucose positron emission tomography showed decreased metabolic activity in frontal lobes, worse on the left. He died at 58 years of age. His family history was notable for early‐onset dementia in a paternal uncle. His father and paternal grandfather died at a young age (Table 1).
Table 1.
Summary of clinical and demographic information of autopsied cases of exon 13 MAPT heterozygous mutations. Abbreviations: AD = Alzheimer's disease; agPPA = agrammatic subtype of primary progressive aphasia; bvFTD = behavioral variant of frontotemporal dementia; CBS = corticobasal syndrome; F = females; L = left; M = males; N/A = not available; neg = negative; pos = positive; R = right; svPPA = semantic subtype of primary progressive aphasia.
| MAPT mutation (Isoform NM_005910.5)[MAPT haplotype] | Sex | Family history of dementia | Disease duration (years) | Age of death (years) | Clinical phenotype* | Parkinsonism |
|---|---|---|---|---|---|---|
| p.E372G (c.1115A>G) [H1/H1] present case | M | Paternal uncle; possibly incomplete penetrance | 18 | 58 | bvFTD | Bradykinesia, neck rigidity |
| p.G389R (c.1165G>C) [H1/H1] 21 8 | M | Paternal uncle and grandfather; possibly incomplete penetrance | 5 | 43 | svPPA | Rigidity, postural and kinetic arm tremor |
| p.G389R (c.1165G>A) [N/A] 23 | F | Negative; possibly incomplete penetrance | 5 | 37 | bvFTD | Rigidity |
| p.G389R (c.1165G>C) [N/A] 4 | F | Paternal uncle, grandfather, great grandfather; variable penetrance (father asymptomatic mutation carrier) | 7 | 24 | bvFTD | Mild tremor, rigidity, and akinesia |
| p.G389R (N/A) [N/A] 2 | F | Maternal grandaunt; possibly incomplete penetrance | 4 | 24 | bvFTD | Absent |
| p.G389R (c.1165G>A) [N/A] 16 | M | N/A | 6 | 22 | bvFTD | Bradykinesia, hypomimia |
| p.G389R (N/A) [N/A] present case 1 | M | Negative | 7 | 31 | agPPA | Absent |
| p.G389R (c.1165G>A) [H1/H1] [N/A] present case 2 | F | Negative | 7 | 60 | bvFTD | L>R bradykinesia (part of CBS) |
| p.R406W (c.1216C>T) [N/A] 26 | M | 14 additional family members | 29 | 76 | Memory impairment | Bradykinesia, rigidity, action and resting arm tremor |
| p.R406W (c.1216C>T) [N/A] 19 | F | 4 additional family members | N/A | N/A | Memory impairment (AD type) | N/A |
| p.R406W (c.1216C>T) [N/A] 33 | M | 5 additional family members | 13 | 70 | Memory impairment | Bradykinesia |
| p.R406W (c.1216C>T) [N/A] 28 | M | Father | 6 | 53 | Paranoid delusions | N/A |
| p.R406W (c.1216C>T) [N/A] 34 | F | Mother, maternal uncle | 12 | 66 | bvFTD (slowly progressive) | Absent |
| p.N410H (c.1228A>C) [H1/H2] 17 | F | Aunt | 4 | 67 | Problems with mood and memory | Bradykinesia, gait freezing, postural hand tremor (part of CBS) |
*Defined on the basis of leading features at the initial clinical presentation.
MAPT p.G389R patient 1
Patient 1 with the p.G389R mutation was a white, right‐handed man with 14 years of education who presented at 24 years of age with memory difficulties and language impairment suggestive of agrammatic variant of primary progressive aphasia (agPPA). He had decreased fluency, agrammatism, and apraxia of speech. He also had subtle changes in personality and behavior that evolved into aggressive behavior and diminished insight. On examination 3 years after symptomatic onset no motor abnormalities were noted, but he had difficulties with learning and abstractions and notable sparing of delayed recall. Two brain MRIs performed near symptomatic onset (Supporting Information Figure 1A,B) and 1 year later (Supporting Information Figure 1C,D) revealed a rapid progression of frontal and temporal atrophy, worse on the left. Single‐photon emission computed tomography showed frontal hypoperfusion, worse on the left. He died at 31 years of age. His family history was negative for neurologic disorders (Table 1).
MAPT p.G389R patient 2
p.G389R patient 2 was a woman with 16 years of education who presented at 53 years of age with changes in behavior and personality consistent with bvFTD. Subsequently, she developed short‐term memory deficits, bradykinesia, and agrammatic speech with repetition, dysarthria and reduced speech output. Other symptoms included decrease in executive functions, pseudobulbar affect, and urinary incontinence. In the end she had showed signs of corticobasal syndrome (CBS), such as left hemi‐apraxia, left side‐predominant bradykinesia, and increased muscle tone with eventual left arm contractions. Brain computed tomography early in the disease showed cortical atrophy and moderate ventriculomegaly. She died at 60 years of age. Her family history was negative for memory disorders. Her parents were first cousins (Table 1).
Neuropathological findings
MAPT p.E372G
The calculated fixed brain weight was 1060 g. There was circumscribed cortical atrophy most marked in frontal and anterior temporal lobes (Figure 2A,B), with enlargement of the lateral ventricle and thinning of the corpus callosum. The hippocampus and amygdala were markedly atrophic. The substantia nigra (Figure 2B, inset) and locus coeruleus had decreased pigmentation.
Figure 2.
Cortical atrophy in MAPT p.G389R and p.E372G mutation carriers. A, B. p.E372G shows moderate frontal cortex atrophy and decreased pigmentation of the substantia nigra (B, inset). C, D. p.G389R case 1 had marked atrophy of the frontal and temporal cortices, extending into superior parietal lobe with mild pallor of the substantia nigra (D, inset). E, F. p.G389R case 2 cortical atrophy pattern is similar to p.E372G, primarily involving the frontal cortex and less severe than p.G389R case 1, with a minimal decrease of pigmentation of the substantia nigra (F, inset). Bar 3 cm (A, C, E) and 1 cm (B, D, F, including insets).
Sections from temporal and frontal lobes, especially the superior frontal gyrus, showed superficial spongiosis and gliosis. The hippocampus had marked neuronal loss, but no TDP‐43‐immunoreactive inclusions (Figure 3A). There was slight myelin pallor of the corticospinal tract at the level of the medulla (Figure 3D), and IBA‐1 IHC showed mild microglial activation (Figure 3D, inset ). There were no Alzheimer type changes. The substantia nigra had marked neuronal loss.
Figure 3.
Neuropathologic features infrequent in MAPT mutation carriers. All three mutations carriers p.E372G (top row), p.G389R case 1 (middle row), and p.G389R case 2 (bottom row) mutation carriers exhibited hippocampal sclerosis A–C and corticospinal tract pathology on LFB (asterisks) D–F. IBA‐1 IHC on the medullary pyramid display microglial morphology (D–F, inset), and tau‐positive neuronal inclusions and neurites in the hypoglossal nucleus G–I. Sections from posterior hippocampus were negative using TDP‐43 IHC (not shown). Bar 2 mm (A–F) and 100 μm (G–I).
Tau IHC revealed tau‐positive neuronal inclusions in small neurons in cortical layer 2, which were negative with thioflavin S fluorescent microscopy (Figure 4A), and tau‐positive threads in white matter that had a swollen, tapered appearance (Figure 4D). There was essentially no glial tau pathology. Pick body‐like (PBL) neuronal inclusions were more immunopositive for 3R (Figure 4B) than for 4R tau (Figure 4C). In addition to neocortex, PBL inclusions were present in hippocampus, amygdala and basal ganglia (Table 2). White matter tapering threads had robust 3R immunoreactivity (Figure 4E), but less 4R immunoreactivity (Figure 4F). PBL inclusions were negative on Gallyas (Figure 5A), but threads were positive (Figure 5B). The density and distribution of tau immunoreactive lesions are shown in Table 3. Tau‐positive neuronal inclusions and neurites were detected in surviving neurons of the substantia nigra and locus coeruleus. The hypoglossal nucleus had numerous tau‐positive neuronal inclusions and dystrophic neurites, but no significant neuronal loss or gliosis (Figure 3G). Swollen tapering threads were present in cerebral peduncle and longitudinal fibers of the pontine base.
Figure 4.
Tau immunohistochemical analyses in p.E372G and p.G389R. Numerous tau‐positive neuronal inclusions, Pick body‐like inclusions, and swollen tapering threads in the white matter of frontal cortex in p.E372G A–F, p.G389R case 1 G–L, and p.G389R case 2 M–R. Top row CP13 antibody against phosphorylated tau, middle row RD3 antibody against 3R isoforms of tau, and bottom row RD4 antibody against 4R isoforms of tau.
Table 2.
Summary of neuropathological, biochemical and functional data of autopsied cases of exon 13 MAPT heterozygous mutations. Abbreviations: 3R = three repeat tau isoform; 4R = four repeat tau isoform; 12E8 = phospho‐tau pSer262 polyclonal antibody; A = astrocytes; AD = Alzheimer's disease; BN = ballooned neurons; Ctx = neocortex; EM = electron microscopy; front = frontal cortex; g = gram; Hp = hippocampus; IHC = tau immunohistochemistry; N/A = not available; neg = negative; NFT = neurofibrillary tangles; NT = neuropil threads; PBL = Pick body‐like inclusions; PHF = paired helical filaments; pos = positive; SF = straight filaments; TB = tau biochemistry (mostly Western blotting of dephosphorylated sarkosyl‐insoluble tau); temp = temporal cortex; wt = weight.
| MAPT mutation | Lobar atrophy; [brain wt.] | Tau isoform composition | Western blot (kDa) | EM Filament (width), [half period] | Neuronal tau pathology* & distribution | Cell type specificity of tau pathology | Microtubule assembly | Tau filament assembly |
|---|---|---|---|---|---|---|---|---|
| p.E372G present case | Severe, esp. frontal, anterior & medial temporal, much less parietal & occipital [1060g] | IHC (PBL inclusions): 3R>4R | major at: 60, 64; minor at: 68 | mostly (15nm) SF, small number of PHF [80‐100nm] | PBL inclusions (not argentophilic on Gallyas) in Ctx (motor, superior frontal, temporal), Hp, & basal ganglia; no BN; no NFT; NT in Ctx (temporal, superior frontal, motor) & basal ganglia; swollen tapering threads in subcortical white matter | Predominantly neuronal | Reduced (for 4R) | Marked increase |
| p.G389R 21 8 | Severe frontal & temporal L > R, incl. Hp & amygdala [N/A] | TB: 3R & 4R † | major at 60, 64; minor at 68, 72 | (13nm) SF > (6‐23nm) twisted filaments [120nm] | PBL inclusions (argentophilic on Bodian, 12E8 pos.) in Ctx (frontal, temporal, cingulate, insular) & Hp (dentate gyrus); occasional NFT‐like inclusions in Ctx; swollen tapering threads in deeper Ctx & subcortical white matter | Predominantly neuronal | Reduced (60% for 3R, 35% for 4R at 2 min.) | N/A |
| p.G389R 23 | Severe frontal & mild temporal (incl. Hp) & parietal [1006g] | TB: 3R<4R † | major at: 60, 64; minor at: 68 | (5‐15nm) SF or twisted filaments [110nm] | PBL inclusions (argentophilic on Palmgren) in Ctx (frontal, temporal, parietal, insular) & Hp (dentate gyrus); occasional NFT‐like inclusions in Ctx; many NT in basal ganglia; swollen tapering threads in deeper Ctx & white matter | Predominantly neuronal | Reduced (25–30% for 4R at 2 min) | N/A |
| p.G389R 4 | Marked frontal & temporal, including moderate Hp [780g] | N/A † | 60, 64, 69 | N/A | PBL inclusions (12E8 pos.) in Ctx (frontal) & Hp (only few in dentate gyrus); swollen tapering threads in subcortical white matter, putamen, & brainstem | Predominantly neuronal | N/A | N/A |
| p.G389R 2 | Severe frontal & temporal, relative sparing of parietal & occipital [944g] | N/A † | N/A | N/A | PBL inclusions in Hp (dentate gyrus); NFT‐like inclusions in Ctx (frontal & inferior temporal); swollen tapering threads in deeper Ctx & throughout white matter | Predominantly neuronal | N/A | N/A |
| p.G389R 16 | Severe frontal, incl. precentral gyri, R > L [N/A] | N/A † | N/A | N/A | PBL inclusions in deeper neocortical layers; swollen tapering threads in subcortical white matter | N/A | N/A | N/A |
| p.G389R present case 1 | Severe anterior temporal > frontal, including primary motor Ctx [770g] | IHC (PBL inclusions): 3R = 4R | N/A | N/A | PBL inclusions (weakly argyrophilic on Gallyas) & NFT‐like inclusions in Ctx, Hp (dentate gyrus), & basal ganglia; swollen tapering threads in deeper Ctx & white matter | Predominantly neuronal | N/A | N/A |
| p.G389R present case 2 | Moderate to marked esp. frontal & temporal (incl. medial temporal); sparing parietal & occipital [740g] | IHC (PBL inclusions): 3R = 4R | major at: 60, 64 minor at: 68 | N/A | PBL inclusions (strongly argyrophilic on Gallyas) in Ctx (temporal, frontal, motor), basal ganglia, Hp, & brainstem; occasional NFT in Ctx (frontal, parietal & motor), less in Hp; NT in Ctx (temporal, frontal, motor), thalamus, basal ganglia; swollen tapering threads in white matter & deeper Ctx | Predominantly neuronal | N/A | N/A |
| p.R406W 26 | Mild symmetric atrophy in frontal & temporal poles & in Hp [1285g] | N/A [Link] , [Link] | N/A | (20‐24nm) PHF [70‐80nm] | No BN; no PB; NFT in Ctx (medial temporal, entorhinal cortex) & Hp, subcortical nuclei, & brainstem; NT in substantia nigra | Predominantly neuronal | N/A ¶ | N/A**,†† |
| p.R406W 19 | Moderate temporal, including Hp [1288g] | IHC: 3R = 4R ‡ | N/A | N/A | No PB; abundant NFT in Ctx (esp. frontal & temporal) & Hp; abundant NT mostly in Hp | Predominantly neuronal | N/A ¶ | N/A**,†† |
| p.R406W 33 | Moderate atrophy of frontal & anterior temporal [1121g] | N/A [Link] , [Link] | 60, 64, 68, 72 | mostly (8‐20nm) PHF [80nm]; small number of (12nm) SF | Few PBL inclusions (12E8 neg.) in Hp (dentate gyrus);abundant NFT in Ctx (frontal, temporal, pyramidal layer, parahippocampal gyrus); extensive NT in Ctx (entorhinal) & Hp | Predominantly neuronal | N/A ¶ | N/A**,†† |
| p.R406W 28 | Frontotemporal accentuated in medial temporal, including subiculum [1380g] | N/A [Link] , [Link] | N/A | PHF ≫ SF | Occasional BN in limbic area & medullary reticular formation; NFT & NT throughout the brain, especially abundant in insular & basal forebrain Ctx, hypothalamus | Predominantly neuronal | N/A ¶ | N/A**,†† |
| p.R406W 34 | Severe in medial temporal R>L, involving Hp, entorhinal Ctx [N/A] | N/A [Link] , [Link] | N/A | N/A | PBL inclusions in Hp (dentate fascia); NFT throughout the brain, esp. in Ctx (temporal, cingulate, frontal), Hp, subcortical nuclei, & dentate nucleus | Predominantly neuronal | N/A ¶ | N/A**,†† |
| p.N410H 17 | Mild atrophy in superior frontal [1000g] | TB: 4R≫3R; IHC: 4R | minor doublet at 37 & major doublet at 64, 68 | (15nm) SF < twisted ribbons [>130 nm] ‡‡ | BN in Ctx (superior frontal); numerous threads & grains in Hp, no NFT in Ctx & Hp | Neuronal and glial (astrocytic plaques, coiled bodies) | Reduced (for 4R: 19.2% decrease of tubulin polymerization rate; 10.3% reduction in extent of total microtubule polymerization) | Marked increased |
*Neuronal tau pathology with neuropil threads.
†IHC (PBL inclusions) in p.G389R: 3R, no 4R 6.
‡TB in p.R406W: 4R = 3R 13.
§IHC (NFT) in p.R406W: 3R = 4R 6.
¶Effect of p.R406W on microtubule assembly: reduced (40% for 3R, 20% for 4R expressed as the optical density at 2 min) 12.
**Effect of p.R406W on tau filament assembly: no stimulatory effect for both 3R & 4R after 48 h 11.
††Effect of p.R406W on tau filament assembly: increased after 4 days of incubation 22.
‡‡Unpublished data, courtesy of Dr W‐L Lin.
Figure 5.
Gallyas silver staining in p.E372G and p.G389R cases. Gallyas silver stain on p.E372G could not detect Pick body‐like inclusions of posterior hippocampus and temporal cortex A, but identified strongly positive threads in temporal cortex white matter B. p.G389R case 1 showed weakly positive Pick body‐like inclusions in the dentate fascia C, arrow and strongly positive threads in temporal cortex white matter D. The Pick body‐like inclusions in the dentate fascia E, arrow and threads F of p.G389R case 2 were strongly positive on Gallyas silver stain. Bar 30 μm (A–F).
Table 3.
Phosphorylated tau‐immunoreactive lesions in p.E372G (CP13 antibody). Abbreviations: 0 = negative; 1 = occasional; 2 = moderate numbers; 3 = frequent numbers; PBL inclusions = Pick body‐like inclusions; pre‐NFT = pre‐tangles.
| Region | PBL inclusions & other tau (+) neuronal inclusions | Tau oligodendrocytes | Tau astrocytes | Tau threads |
|---|---|---|---|---|
| Temporal cortex | 1 | 0 | 0 | 2 |
| Superior frontal cortex | 1 | 0 | 0 | 3 |
| Motor cortex | 2 | 0 | 0 | 3 |
| Caudate/putamen | 3 | 0 | 0 | 3 |
| Globus pallidus | 1 | 0 | 0 | 2 |
| Basal nucleus | 0 | 0 | 0 | 1 |
| Hypothalamus | 1 | 0 | 0 | 1 |
| Ventral thalamus | 0 | 0 | 0 | 1 |
| Subthalamic nucleus | 1 | 0 | 0 | 0 |
| Thalamic fasciculus | 0 | 0 | 0 | 2 |
| Red nucleus | 1 | 0 | 0 | 0 |
| Substantia nigra | 2 | 0 | 0 | 0 |
| Oculomotor complex | 1 | 0 | 0 | 0 |
| Midbrain tectum | 0 | 0 | 0 | 1 |
| Locus coeruleus | 1 | 0 | 0 | 0 |
| Pontine tegmentum | 0 | 0 | 0 | 0 |
| Pontine base | 0 | 0 | 0 | 2 |
| Medullary tegmentum | 1 | 0 | 0 | 0 |
| Inferior olive | 0 | 0 | 0 | 0 |
| Dentate nucleus | 0 | 0 | 0 | 0 |
| Cerebellar white matter | 0 | 0 | 0 | 1 |
MAPT p.G389R case 1
The total fixed brain weight was 770 g. There was severe atrophy of frontal and anterior temporal lobes (Figure 2C,D). The caudate nucleus had atrophy, and there was mild pallor of the substantia nigra (Figure 2D, inset). Sections from frontal cortex showed status spongiosis. There was hippocampal atrophy with neuronal loss and gliosis (Figure 3B), but no TDP‐43‐immunoreactive inclusions (not shown). There was no Alzheimer type pathology or amyloid angiopathy. There was marked corticospinal tract degeneration (Figure 3E) associated with gliosis and Rosenthal fibers (Supporting Information Figure 2). Thalamic nuclei and the substantia nigra had marked neuronal loss and gliosis with scattered pleomorphic intraneuronal and thread‐like tau‐immunoreactive deposits. There were numerous tau‐positive neuronal inclusions and threads in the hypoglossal nucleus (Figure 3H) and anterior horn cells of the spinal cord, but no significant motor neuron loss.
Tau‐positive neuronal inclusions and PBL inclusions (Figure 4G) were positive for both 3R (Figure 4H) and 4R tau (Figure 4I). PBL inclusions were detected in neocortex, dentate fascia of the hippocampus, and basal ganglia (Table 2). There were swollen, tapering tau‐positive threads in white matter (Figure 4J–L). Astroglial and oligodendroglial tau inclusions were minimal. There was weak argyrophilia of PBL inclusions (Figure 5C) and strong staining of swollen tapering threads in white matter with Gallyas silver stain (Figure 5D).
MAPT p.G389R case 2
The calculated fixed brain weight was 740 g. There was cortical atrophy in the frontal, temporal, and medial temporal lobe (Figure 2E,F). There was mild pallor of the substantia nigra (Figure 2F, inset) and marked enlargement of frontal and temporal horns of the lateral ventricle. The hippocampus and amygdala had marked atrophy.
The anteromedial temporal, frontal, and superior frontal cortices had atrophy with superficial spongiosis and gliosis. White matter had mild myelin staining pallor and vacuolation, most marked in frontal and motor cortices. The corpus callosum was thin and had fiber loss. There was no Alzheimer type pathology. The substantia nigra had neuronal loss. The hippocampus had severe neuronal loss and gliosis in CA1 and the subiculum (Figure 3C). PBL inclusions (Figure 5E) and swollen tapering threads in white matter (Figure 5F) were both strongly positive with Gallyas stain. The caudate and nucleus accumbens, as well as the dorsomedial thalamus had atrophy and gliosis. There was corticospinal tract degeneration (Figure 3F).
Tau IHC revealed tau‐positive inclusions in many neurons (Figure 4M), especially in layers 2 and 3 and at the gray‐white junction. There were many swollen tapering threads in white matter (Figure 4P) that were strongly immunoreactive for both 3R (Figure 4N,Q) and 4R tau (Figure 4O,R). Astroglial and oligodendroglial tau pathology was minimal. Tau IHC showed PBL inclusions in hippocampal pyramidal neurons and the dentate fascia, as well as in the entorhinal cortex, amygdala, substantia nigra, locus coeruleus, and hypoglossal nucleus (Figure 3I) (Table 2). Many swollen threads were observed in the cerebral peduncle and longitudinal fibers of the pontine base.
Electron microscopy of swollen tapering threads in MAPT p.E372G
There were two types of swollen tapered cell processes in frontal white matter. The most frequent had bundles of filaments with vacuoles that contained electron dense granular material. The less frequent type had densely packed filaments without vacuoles (Figure 6A–C). Both types of processes were unmyelinated. The majority of the filaments were straight, with a diameter of approximately 15 nm. Mixed with straight filaments, were a smaller number of paired helical filaments (PHF) with a half‐periodicity of 80‐100 nm (Figure 6E). Immunoelectron microscopy showed that the filaments in both types of processes were composed of phospho‐tau (Figure 6D,E).
Figure 6.
Electron micrographs of three swollen tapering threads, all are unmyelinated. A. Process is packed with filaments. B. Process has degradation material in spaces between bundles of filaments. C. This swollen process has more space with debris, and smaller bundles of filaments. Note break in the plasma membrane (arrow). Immunogold labeling of p.E372G filaments with PHF1. D. Arrows point to some of 18 nm gold particles. Arrowhead points to enlarged area shown on the right. E. A twisted filament with a half‐periodicity of <100 nm among many straight filaments of ∼15 nm in diameter. Bar 1 μm (A–C), Bar 0.1 μm (D), Bar 50 nm (E).
Functional and biochemical studies of MAPT p.E372G
The functional effects of the p.E372G mutation were assessed on tau filament formation. Ninety minutes after inducing aggregation, p.E372G recombinant tau showed marked increase in number and length of filaments compared with WT tau (Figure 7A,B). The number of filaments and their lengths was assessed and there was more than a six‐fold increase in the number of filaments for p.E372G tau compared with WT tau (P = 7.6 × 10−11) (Figure 7C), and there was concomitant increase in filament length for p.E372G tau (164.3 ± 69.1 nm) compared with WT tau (126.2 ± 36.2 nm) (P = 4.7 × 10−31) (Figure 7D). Filament formation for the p.G389R mutation could not be quantified due to the high propensity for the filaments to aggregate.
Figure 7.
In vitro tau filament formation and tubulin polymerization in WT tau and p.E372G tau. Upon treatment of recombinant tau with polyglycosaminoglycan, representative electron micrographs of WT tau A and p.E372G tau B at 90 min show the extent of filament formation. p.E372G tau showed a marked increase in filament number C and the average filament length was longer for p.E372G tau D. Representative electron micrographs 90 min after inducing aggregation without sonication of p.E372G recombinant tau, formed long filamentous structures some of which were clustered together in round formations E, and p.G389R showed tau filaments assembled into round Pick body‐like inclusions F. Tubulin polymerization assays were performed to assess MT assembly properties of p.E372G tau and shows a mild decrease compared with WT tau, but a significant decrease in steady‐state microtubule polymerization G. Bar graphs represent the average of nine EM images per genotype per time point and error bars are the SEM. *P<0.0001.
To determine the filamentous structure of mutant tau, p.E372G and p.G389R were introduced into 4R0N recombinant tau protein. Recombinant tau was treated with polyglycosaminoglycan to induce aggregation without sonication and visualized with EM. The p.G389R mutant tau filaments assembled into well‐circumscribed, round structures with very few unassembled filaments (Figure 7F). Tau with p.E372G mutation formed similar round structures, although they were less compact compared with p.G389R, and also had a mixture of straight tau filaments (Figure 7E).
The effects of p.E372G mutation on its ability to promote in vitro microtubule assembly were compared with WT tau. Both p.E372G and WT in 4R0N tau promoted microtubule assembly at approximately the same rates, but the steady‐state microtubule polymerization at 20 min was decreased for p.E372G tau compared with WT tau (Figure 7G). This is consistent with published data for p.G389R 21, 23.
Sarkosyl‐insoluble tau proteins were extracted from gray and white matter of frontal and temporal cortices of the p.E372G and p.G389R case 2 and studied with Western blot analysis. Insoluble tau was greater in p.G389R than p.E372G as indicated by IHC analysis (Figure 4A,D,M,P). After normalization of tau loading, p.E372G and p.G389R had similar tau banding pattern with major bands at 60 and 64 kDa and a minor band at 68 kDa (Figure 8E,F). This suggests that insoluble tau contains both 3R and 4R tau isoforms. In contrast, samples purified from p.P301L showed bands predominantly at 64 and 68 kDa. The filament morphologies of p.E372G case and p.G389R case 2 with EM were quite similar. They had a mixture of straight filaments as observed in p.P301L and less abundant PHFs with a greater periodicity and less compact structure compared with AD PHF (Figure 8A–D).
Figure 8.
Biochemical analysis of insoluble tau. Preparations of sarkosyl‐insoluble tau from frontal cortex of the p.E372G case confirm the presence of both straight filaments A and paired helical filaments B. Sarkosyl‐insoluble tau extracted from frontal cortex of p.G389R case 2, also show straight C and paired helical filaments D which are not readily distinguishable from p.E372G by electron microscopy. Western blotting of sarkosyl‐insoluble tau from frontal cortex E and temporal cortex F in gray matter (G) and white matter (W) with a total tau antibody, demonstrates that both p.E372G and p.G389R contain insoluble tau species predominantly at 60 and 64 kDa bands with lighter bands at 68 kDa. The positioning of these bands is almost identical between these cases and between gray and white matter though there is a faint band at approximately 63 kDa in the gray matter of p.G389R case. This contrasts to the 4R tauopathy harboring the p.P301L mutation with bands predominantly at 64 and 68 kDa. Bar 50 nm (A–D).
Discussion
We describe a patient with FTDP‐17 and a novel MAPT mutation in exon 13, p.E372G, at a highly conserved amino acid residue. We compare our patient with two patients with another exon 13 mutation, p.G389R. Although we were unable to test other family members to show segregation, functional studies provide support for this being a pathogenic mutation. In addition, 1224 normal controls were negative for this mutation, and it was not present in either dbSNP, Exome Variant Server, or 1000 Genomes databases.
Clinically, the p.E372G patient and the two p.G389R patients presented with changes in behavioral and personality, as well as agrammatic speech, but the temporal sequence of the symptoms, age of onset, and disease duration varied between the patients (Table 1). The p.E372G patient presented with bvFTD in the fourth decade of life with subsequent agrammatic speech production and a longer disease duration. The p.E372G patient and p.G389R patient 2 both had parkinsonism and the p.E372G patient also had signs of pyramidal tract dysfunction. The absence of pyramidal and extrapyramidal features in patient 1 with p.G389R could be due to lack of neurological documentation later in the patients' disease course.
The neuropathologic findings were strikingly similar between p.E372G and p.G389R, and characterized by PBL neuronal inclusions, as well as numerous tau‐positive swollen tapering thread‐like processes in white matter 2, 4, 8, 16, 21, 23. To our knowledge, the latter was previously considered a unique feature for p.G389R, but it can also be seen in FTDP‐17 due to p.E372G. This histopathologic feature suggests high likelihood of MAPT exon 13 mutation.
Of note, the p.E372G patient had less severe pathology despite a longer disease duration compared with the two p.G389R patients. Caudate nucleus atrophy was marked in p.G389R, but minimal in p.E372G. Both p.G389R patients had frontotemporal atrophy that was more severe in the anterior temporal regions than in the frontal lobes. By contrast, the p.E372G patient had predominantly frontal atrophy. In all three had severe neuronal loss and gliosis in the substantia nigra, hippocampal atrophy and corticospinal tract degeneration. To our knowledge, corticospinal tract degeneration is a relatively uncommon feature of FTDP‐17, but has been reported in a few MAPT mutations, both at autopsy (p.K317N 32, p.K317M 36, p.N279K 35, c.1883 + 14C > T 20) and on brain MRI (p.G389R 27).
The PBL inclusions in FTDP‐17 due to p.E372G were negative on Gallyas and had more 3R tau than 4R tau immunoreactivity, as expected for sporadic Pick's disease. In contrast, PBL inclusions in both patients with p.G389R were strongly positive for both 3R tau and 4R tau and showed either weak (case 1) or strong (case 2) argyrophilia with Gallyas, features that are atypical for Pick's disease.
Ultrastructural studies showed differences in the morphology of swollen tapered processes in p.E372G compared with previous reports of p.G389R 21, 23. Previous ultrastructural studies of p.G389R described cell processes with densely packed filaments 21, 23. Interestingly, they were from patients with relatively short disease durations (approximately 5 years) (Table 1). In p.E372G, abnormal tau filaments were detected in unmyelinated cell processes, while the previous studies of p.G389R showed filaments in myelinated axons. We did not observe abnormal tau filaments in myelinated axons, but we did find axons with dense accumulations of neurofilaments. In p.E372G, the filaments were mostly straight, with a few twisted filaments with a half‐periodicity of <100 nm, similar to Alzheimer‐type PHF. EM findings of p.G389R were similar in this regard 8, 21, 23 (Table 2).
Biochemical analyses of insoluble tau showed similarities between p.G389R and p.E372G with tau band at 60 and 64 kDa and a minor band at 68 kDa, indicating presence of both 3R and 4R tau isoforms in insoluble tau.
Unlike previously reported carriers of the heterozygous p.G389R mutation 2, 4, 8, 21, 23, there was no family history of dementia in either of our p.G389R patients. In contrast the family history of FTDP‐17 due to p.E372G was remarkable for early‐onset dementia in a paternal uncle, while his father and paternal grandfather were free of memory problems. It should be noted, however, that both died at a young age. Nevertheless, the paucity of positive family history raises the possibility of incomplete penetrance as previously reported in p.G389R mutation carriers 2, 4, 8, 21, 23, 27 (Table 1). Germ‐line mosaicism, which may have arisen during oogenesis or spermatogenesis of non‐mutation carrying parents, offers an alternative explanation. It has previously been reported in the MAPT p.S305N mutation 3.
This novel p.E372G mutation is the fifth mutation exon 13 9. Of these p.G389R, p.E372G, and p.R406W are characterized by tau pathology predominantly affecting neurons and a frontotemporal atrophy pattern. While p.G389R and p.E372G had pathologic features similar to Pick's disease, the neurofibrillary tangles in p.R406W were similar to AD or tangle predominant dementia. Insoluble tau was composed of all six tau isoforms and a 3R and 4R tau ratio of 1:1 13, 34. These contrast with extensive glial and neuronal tau pathology in another exon 13 MAPT mutation, p.N410H 17, which was indistinguishable from sporadic CBD. IHC and Western blot studied of p.N410H showed predominance of 4R tau and EM demonstrated mostly long‐periodicity twisted ribbons (Table 2).
These four exon 13 mutations all show decreased ability to promote microtubule assembly. The p.E372G and p.N410H mutations also markedly increase tau filament formation, whereas the reported effect of the p.R406W mutation on tau filament formation was minimal 11, 22. The latter may explain a longer disease duration and milder phenotype in FTDP‐17 due to p.R406W (Table 1). No data on tau filament assembly is available for p.G389R (Table 2).
Another exon 13 mutation, p.T427M, is lacking neuropathologic studies, but the clinical picture is consistent with frontotemporal dementia 10, which is also common for p.E372G and p.G389R and some patients with p.R406W mutations 34. Other clinical phenotypes of p.R406W have progressive psychosis 28 and Alzheimer‐type dementia 15, 25. The N410H carrier 17 and the p.G389R case 2 from this study and another previously reported p.G389R carrier 27 presented with CBS. It is worth noting that parkinsonism is common in patients with exon 13 MAPT mutations (Table 1).
While we were unable to show segregation of the mutation in this family, we were able to show a pathologic effect of the p.E372G mutation and suggest that its pathogenic effects is based on at least two mechanisms: decreased ability of mutant tau to promote microtubule assembly and markedly increase in filament formation. The similarities between p.E372G and p.G389R both clinically and pathologically, as well as the biochemical and functional consequences of the p.E372G codon change, suggest that the mutation is indeed pathogenic.
Supporting information
Additional Supporting Information may be found in the online version of this article at the publisher's web‐site:
Figure S1. Brain magnetic resonance imaging from the p.G389R patient 1. A. T1‐weighted coronal brain magnetic resonance imaging (MRI) and B mid‐sagittal MRI during first year of disease course did not reveal significant atrophy patterns. C. One year later in the second year of p.G389R patient's disease course, MRI scan shows enlargement of lateral ventricles (asterisks), atrophy of the temporal lobe (arrow), D atrophy of the frontal lobe (arrowhead), and thinning of the corpus callosum (arrow).
Figure S2. Rosenthal fibers in p.G389R case 2. Hematoxylin and eosin stain of the corticospinal tract at the level of the medullary pyramid shows Rosenthal fibers (arrow).
Supporting Information
Supporting Information
Acknowledgments
The authors would like to thank all patients and their families for support of this research. We would also like to thank Monica Castanedes Casey, Linda Rousseau and Virginia Phillips for histological and immunohistochemistry. Joseph R. Duffy for speech evaluation of Patient 2 and Amanda M. Serie for assistance with image analysis. This work was funded by the Mayo Foundation (Robert E. Jacoby Professorship of Alzheimer's Research) and NIH grants: P50‐AG016574, P50‐NS072187. The Society for Progressive Supranuclear Palsy Brain Bank is supported by CurePSP. NK is supported by a postdoctoral fellowship from Karin & Sten Mortstedt CBD Solutions AB. PT is supported by a Jaye F. and Betty F. Dyer Foundation Fellowship in progressive supranuclear palsy research, a Max Kade Foundation postdoctoral fellowship, an Allergan Medical Educational Grant and a gift from Carl Edward Bolch, Jr, and Susan Bass Bolch. RR is supported by Peebler PSP Research Foundation and NIH P50 NS072187. KAJ is supported by the NIH grants R01‐AG037491, R01‐NS89757, and R01‐AG50603. ZKW is partially supported by the NIH/NINDS P50 NS072187, the Mayo Clinic Center for Regenerative Medicine, the Mayo Clinic Center for Individualized Medicine, the Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research of Mayo Clinic in Florida), and the Sol Goldman Charitable Trust. MEM is supported by the Florida Department of Health, Ed and Ethel Moore Alzheimer's Disease Research Program (6AZ01). KMH is partially supported by the Florida Department of Elder Affairs and also receives support from the Research Service of the Veterans Affairs Medical Center, Gainesville, and NIH.
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Associated Data
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Supplementary Materials
Additional Supporting Information may be found in the online version of this article at the publisher's web‐site:
Figure S1. Brain magnetic resonance imaging from the p.G389R patient 1. A. T1‐weighted coronal brain magnetic resonance imaging (MRI) and B mid‐sagittal MRI during first year of disease course did not reveal significant atrophy patterns. C. One year later in the second year of p.G389R patient's disease course, MRI scan shows enlargement of lateral ventricles (asterisks), atrophy of the temporal lobe (arrow), D atrophy of the frontal lobe (arrowhead), and thinning of the corpus callosum (arrow).
Figure S2. Rosenthal fibers in p.G389R case 2. Hematoxylin and eosin stain of the corticospinal tract at the level of the medullary pyramid shows Rosenthal fibers (arrow).
Supporting Information
Supporting Information