Publications by authors named "Helena Gossye"

8 Publications

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Family-based exome sequencing identifies RBM45 as a possible candidate gene for frontotemporal dementia and amyotrophic lateral sclerosis.

Neurobiol Dis 2021 Aug 9;156:105421. Epub 2021 Jun 9.

Neurodegenerative Brain Diseases, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Institute Born-Bunge, Antwerp, Belgium. Electronic address:

Neurodegenerative disorders like frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are pathologically characterized by toxic protein deposition in the cytoplasm or nucleus of affected neurons and glial cells. Many of these aggregated proteins belong to the class of RNA binding proteins (RBP), and, when mutated, account for a significant subset of familial ALS and FTD cases. Here, we present first genetic evidence for the RBP gene RBM45 in the FTD-ALS spectrum. RBM45 shows many parallels with other FTD-ALS associated genes and proteins. Multiple lines of evidence have demonstrated that RBM45 is an RBP that, upon mutation, redistributes to the cytoplasm where it co-aggregates with other RBPs into cytoplasmic stress granules (SG), evolving to persistent toxic TDP-43 immunoreactive inclusions. Exome sequencing in two affected first cousins of a heavily affected early-onset dementia family listed a number of candidate genes. The gene with the highest pathogenicity score was the RBP gene RBM45. In the family, the RBM45 Arg183* nonsense mutation co-segregated in both affected cousins. Validation in an unrelated patient (n = 548) / control (n = 734) cohort identified an additional RBM45 Arg183* carrier with bvFTD on a shared 4 Mb haplotype. Transcript and protein expression analysis demonstrated loss of nuclear RBM45, suggestive of a loss-of-function disease mechanism. Further, two more ultra-rare VUS, one in the nuclear localization signal (NLS, p.Lys456Arg) in an ALS patient and one in the intrinsically disordered homo-oligomer assembly (HOA) domain (p.Arg314Gln) in a patient with nfvPPA were detected. Our findings suggest that the pathomechanisms linking RBM45 with FTD and ALS may be related to its loss of nuclear function as a mediator of mRNA splicing, cytoplasmic retention or its inability to form homo-oligomers, leading to aggregate formation with trapping of other RBPs including TDP-43, which may accumulate into persisted TDP-43 inclusions.
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http://dx.doi.org/10.1016/j.nbd.2021.105421DOI Listing
August 2021

Hippocampal Sclerosis in Frontotemporal Dementia: When Vascular Pathology Meets Neurodegeneration.

J Neuropathol Exp Neurol 2021 Mar;80(4):313-324

Institute Born-Bunge, Neuropathology and Laboratory of Neurochemistry and Behavior, University of Antwerp, Antwerp, Belgium.

Hippocampal sclerosis (HS) is a common neuropathological finding and has been associated with advanced age, TDP-43 proteinopathy, and cerebrovascular pathology. We analyzed neuropathological data of an autopsy cohort of early-onset frontotemporal dementia patients. The study aimed to determine whether in this cohort HS was related to TDP-43 proteinopathy and whether additional factors could be identified. We examined the relationship between HS, proteinopathies in frontotemporal cortices and hippocampus, Alzheimer disease, cerebrovascular changes, and age. We confirmed a strong association between HS and hippocampal TDP-43, whereas there was a weaker association between HS and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Nearly all of the FTLD-TDP cases had TDP-43 pathology in the hippocampus. HS was present in all FTLD-TDP type D cases, in 50% of the FTLD-TDP A cohort and in 6% of the FTLD-TDP B cohort. Our data also showed a significant association between HS and vascular changes. We reviewed the literature on HS and discuss possible pathophysiological mechanisms between TDP-43 pathology, cerebrovascular disease, and HS. Additionally, we introduced a quantitative neuronal cell count in CA1 to objectify the semiquantitative visual appreciation of HS.
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http://dx.doi.org/10.1093/jnen/nlab010DOI Listing
March 2021

No association of CpG SNP rs9357140 with onset age in Belgian C9orf72 repeat expansion carriers.

Neurobiol Aging 2021 01 15;97:145.e1-145.e4. Epub 2020 Aug 15.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address:

We investigated the impact of the recently described chromosome 6 open reading frame 10 (C6orf10)/LOC101929163 locus as age-at-onset modifier in an extended cohort of Belgian chromosome 9 open reading frame 72 (C9orf72) GC repeat expansion carriers. We genotyped the tagging CpG single-nucleotide polymorphism rs9357140 in 224 confirmed C9orf72 repeat expansion carriers, 102 index cases and 122 relatives, and tested association with onset age. The C9orf72 repeat expansion cohort consisted of 131 symptomatic carriers, that is, 78 with dementia only, 13 with frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS), and 40 ALS only, and 93 presymptomatic carriers. Cox proportional hazard regression analysis failed to identify significant association (adjusted hazard ratio = 1.15, p = 0.3). We further extended our analysis to a Belgian cohort of unrelated, mutation-negative FTD index patients (n = 230), but also found no association (adjusted hazard ratio = 0.96, p = 0.3). Overall, our findings suggest that in the Belgian cohort, the C6orf10/LOC101929163 locus cannot explain the marked variability in age at onset, and other genetic or environmental modifiers must drive the clinical heterogeneity observed among C9orf72 repeat expansion carriers.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.07.021DOI Listing
January 2021

Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export.

Acta Neuropathol 2020 06 14;139(6):1001-1024. Epub 2020 Mar 14.

Center for Molecular Neurology, VIB, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.

Parkinson's disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver.
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http://dx.doi.org/10.1007/s00401-020-02145-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244618PMC
June 2020

The Use of Biomarkers and Genetic Screening to Diagnose Frontotemporal Dementia: Evidence and Clinical Implications.

Front Neurosci 2019 6;13:757. Epub 2019 Aug 6.

Institute Born - Bunge, University of Antwerp, Antwerp, Belgium.

Within the wide range of neurodegenerative brain diseases, the differential diagnosis of frontotemporal dementia (FTD) frequently poses a challenge. Often, signs and symptoms are not characteristic of the disease and may instead reflect atypical presentations. Consequently, the use of disease biomarkers is of importance to correctly identify the patients. Here, we describe how neuropsychological characteristics, neuroimaging and neurochemical biomarkers and screening for causal gene mutations can be used to differentiate FTD from other neurodegenerative diseases as well as to distinguish between FTD subtypes. Summarizing current evidence, we propose a stepwise approach in the diagnostic evaluation. Clinical consensus criteria that take into account a full neuropsychological examination have relatively good accuracy (sensitivity [se] 75-95%, specificity [sp] 82-95%) to diagnose FTD, although misdiagnosis (mostly AD) is common. Structural brain MRI (se 70-94%, sp 89-99%) and FDG PET (se 47-90%, sp 68-98%) or SPECT (se 36-100%, sp 41-100%) brain scans greatly increase diagnostic accuracy, showing greater involvement of frontal and anterior temporal lobes, with sparing of hippocampi and medial temporal lobes. If these results are inconclusive, we suggest detecting amyloid and tau cerebrospinal fluid (CSF) biomarkers that can indicate the presence of AD with good accuracy (se 74-100%, sp 82-97%). The use of P-tau and the Aβ /Aβ ratio significantly increases the accuracy of correctly identifying FTD vs. AD. Alternatively, an amyloid brain PET scan can be performed to differentiate FTD from AD. When autosomal dominant inheritance is suspected, or in early onset dementia, mutation screening of causal genes is indicated and may also be offered to at-risk family members. We have summarized genotype-phenotype correlations for several genes that are known to cause familial frontotemporal lobar degeneration, which is the neuropathological substrate of FTD. The genes most commonly associated with this disease () are discussed, as well as some less frequent ones (). Several other techniques, such as diffusion tensor imaging, tau PET imaging and measuring serum neurofilament levels, show promise for future implementation as diagnostic biomarkers.
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http://dx.doi.org/10.3389/fnins.2019.00757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691066PMC
August 2019

Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability.

Acta Neuropathol 2019 06 14;137(6):901-918. Epub 2019 Mar 14.

Center for Molecular Neurology, VIB, Antwerp, Belgium.

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frameshift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate.
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http://dx.doi.org/10.1007/s00401-019-01976-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531610PMC
June 2019

Use of hyperthermia versus normothermia during intraperitoneal chemoperfusion with oxaliplatin for colorectal peritoneal carcinomatosis: A propensity score matched analysis.

Eur J Surg Oncol 2019 03 6;45(3):366-370. Epub 2018 Sep 6.

Department of GI Surgery, Ghent University Hospital, Cancer Research Institute Ghent (CRIG), Belgium. Electronic address:

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (OX) is increasingly used in the treatment of colorectal peritoneal carcinomatosis (PC). However, the additional benefit of hyperthermia remains clinically unproven, while it may aggravate postoperative morbidity. Here, we report the correlation of perfusion temperature with postoperative morbidity during clinical HIPEC with OX.

Patients And Methods: Patients who underwent hyperthermic (41 °C, HT) or normothermic (37 °C, NT) chemoperfusion with OX for colorectal PC were identified from a prospectively kept database of HIPEC cases and matched for baseline characteristics using propensity score (PS) analysis. The groups were compared to assess the impact of perfusion temperature on morbidity. Morbidity was graded using the Clavien-Dindo (CD) classification and the Comprehensive Complication Index (CCI).

Results: Out of 612 patients, 146 patients met the inclusion criteria and from these patients, 45 HT patients were matched with 45 NT patients. Baseline variables were comparable between the PS matched groups. Overall mortality was 0.7% and major morbidity (CD ≥ 3) occurred in 35,6% of patients. There were no significant differences between the HT and NT cohorts in mortality, major morbidity (RR 1.33, 95% CI 0.71 to 2.49, p = 0.36), anastomotic leakage (13.8% versus 11.1%, p = 1.0), hemorrhagic complications, or systemic toxicity. A trend of increased wound infections was observed in the hyperthermia group (13.3% versus 4.4%, P = 0.27).

Conclusions: Compared to NT, the use of HT during HIPEC with OX does not aggravate postoperative mortality or morbidity in a high-volume center.
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http://dx.doi.org/10.1016/j.ejso.2018.08.023DOI Listing
March 2019
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