The wide genetic landscape of clinical frontotemporal dementia: systematic combined sequencing of 121 consecutive subjects

Blauwendraat, Cornelis; Wilke, Carlo; Simón‐Sánchez, Javier; Jansen, Iris E.; Reifschneider, Anika; Capell, Anja; Haass, Christian; Castillo-Lizardo, Melissa; Biskup, Saskia; Maetzler, Walter; Rizzu, Patrizia; Heutink, Peter; Synofzik, Matthis

doi:10.1038/gim.2017.102

Cited by 63 publications

(48 citation statements)

References 43 publications

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“…Surprisingly, levels of p‐tau ant t‐tau were increased in all three, with decreased levels of Aβ42 only in one of them. Several previous reports have described diminished CSF Aβ levels in sporadic or/and genetic FTLD . It is discussed whether this finding is related to an increased deposition of Aβ spices or to a reduction of Aβ production, as it is associated with a reduction in soluble APP levels.…”

Section: Discussionmentioning

confidence: 86%

Novel P397S MAPT variant associated with late onset and slow progressive frontotemporal dementia

Borrego‐Écija

Antonell

Puig-Butillé

et al. 2019

Ann Clin Transl Neurol

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Mutations in the MAPT gene cause frontotemporal dementia with tau deposits. We report the novel p.P397S MAPT variant in eight subjects from five apparently nonrelated families suffering from frontotemporal dementia with autosomal dominant pattern of inheritance. In silico analysis reported conflicting evidence of pathogenicity. The segregation analysis support that this variant is likely pathogenic. The mean age at onset (61.4 years) and mean disease duration (13.9 years) of these subjects and their affected relatives were significantly higher compared with our series of p.P301L MAPT mutation carriers. These findings suggest that p.P397S variant could be a new MAPT mutation associated with a less aggressive phenotype than other MAPT mutations.

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Section: Discussionmentioning

confidence: 86%

Novel P397S MAPT variant associated with late onset and slow progressive frontotemporal dementia

Borrego‐Écija

Antonell

Puig-Butillé

et al. 2019

Ann Clin Transl Neurol

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“…Autosomal dominant inherited cases often occur clustered in families [ 13 ]. The large majority of sporadic FTLD cases is, however, of unknown etiology, albeit genetic alterations are to be expected there too [ 14 ]. The behavioural variant (bvFTD) accounts for more than half of the cases [ 15 ] and is histopathologically described by distinct inclusion bodies either comprised of Tau (FTLD-TAU) [ 16 ] or ubiquitinated TDP-43 (FTLD-TDP) [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Specific serum and CSF microRNA profiles distinguish sporadic behavioural variant of frontotemporal dementia compared with Alzheimer patients and cognitively healthy controls

et al. 2018

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Information on circulating miRNAs in frontotemporal lobar degeneration is very limited and conflicting results have complicated an interpretation in Alzheimer’s disease thus far. In the present study we I) collected samples from multiple clinical centers across Germany, II) defined 3 homogenous patient groups with high sample sizes (bvFTD n = 48, AD n = 48 and cognitively healthy controls n = 44), III) compared expression levels in both CSF and serum samples and IV) detected a limited set of miRNAs by using a MIQE compliant protocol based on SYBR-green miRCURY assays that have proven reliable to generate reproducible results. We included several quality controls that identified and reduced technical variation to increase the reliability of our data. We showed that the expression levels of circulating miRNAs measured in CSF did not correlate with levels in serum. Using cluster analysis we found expression pattern in serum that, in part, reflects the genomic organization and affiliation to a specific miRNA family and that were specifically altered in bvFTD, AD, and control groups. Applying factor analysis we identified a 3-factor model characterized by a miRNA signature that explained 80% of the variance classifying healthy controls with 97%, bvFTD with 77% and AD with 72% accuracy. MANOVA confirmed signals like miR-320a and miR-26b-5p at BH corrected significance that contributed most to discriminate bvFTD cases with 96% sensitivity and 90% specificity and AD cases with 89% sensitivity and specificity compared to healthy controls, respectively. Correlation analysis revealed that miRNAs from the 3-factor model also correlated with levels of protein biomarker amyloid-beta1-42 and phosphorylated neurofilament heavy chain, indicating their potential role in the monitoring of progressive neuronal degeneration. Our data show that miRNAs can be reproducibly measured in serum and CSF without pre-amplification and that serum includes higher expressed signals that demonstrate an overall better ability to classify bvFTD, AD and healthy controls compared to signals detected in CSF.

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“…The typical age‐of‐onset in these families is in the fifties, and patients show variable clinical presentation and disease duration (1–12 years). Sequencing studies identified several other CHCHD10 mutations in ALS/FTD cohorts, but lack functional characterization to support pathogenicity (Chaussenot et al , ; Dols‐Icardo et al , ; Zhang et al , ; Jiao et al , ; Zhou et al , ; Blauwendraat et al , ).…”

Section: Introductionmentioning

confidence: 99%

A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

et al. 2018

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CHCHD10 mutations are linked to amyotrophic lateral sclerosis, but their mode of action is unclear. In a 29‐year‐old patient with rapid disease progression, we discovered a novel mutation (Q108P) in a conserved residue within the coiled‐coil‐helix‐coiled‐coil‐helix (CHCH) domain. The aggressive clinical phenotype prompted us to probe its pathogenicity. Unlike the wild‐type protein, mitochondrial import of CHCHD10 Q108P was blocked nearly completely resulting in diffuse cytoplasmic localization and reduced stability. Other CHCHD10 variants reported in patients showed impaired mitochondrial import (C122R) or clustering within mitochondria (especially G66V and E127K) often associated with reduced expression. Truncation experiments suggest mitochondrial import of CHCHD10 is mediated by the CHCH domain rather than the proposed N‐terminal mitochondrial targeting signal. Knockdown of Mia40, which introduces disulfide bonds into CHCH domain proteins, blocked mitochondrial import of CHCHD10. Overexpression of Mia40 rescued mitochondrial import of CHCHD10 Q108P by enhancing disulfide‐bond formation. Since reduction in CHCHD10 inhibits respiration, mutations in its CHCH domain may cause aggressive disease by impairing mitochondrial import. Our data suggest Mia40 upregulation as a potential therapeutic salvage pathway.

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The wide genetic landscape of clinical frontotemporal dementia: systematic combined sequencing of 121 consecutive subjects

Cited by 63 publications

References 43 publications

Novel P397S MAPT variant associated with late onset and slow progressive frontotemporal dementia

Novel P397S MAPT variant associated with late onset and slow progressive frontotemporal dementia

Specific serum and CSF microRNA profiles distinguish sporadic behavioural variant of frontotemporal dementia compared with Alzheimer patients and cognitively healthy controls

A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS

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