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Comprehensive mRNA Expression Profiling Distinguishes Tauopathies and Identifies Shared Molecular Pathways

Iraad F. Bronner, Zoltán Bochdanovits, Patrizia Rizzu, Wouter Kamphorst, Rivka Ravid, John C. van Swieten, Peter Heutink, Mark R. Cookson
2009 PLoS ONE  
Understanding the aetiologies of neurodegenerative diseases such as Alzheimer's disease (AD), Pick's disease (PiD), Progressive Supranuclear Palsy (PSP) and Frontotemporal dementia (FTD) is often hampered by the considerable clinical and molecular overlap between these diseases and normal ageing. The development of high throughput genomic technologies such as microarrays provide a new molecular tool to gain insight in the complexity and relationships between diseases, as they provide data on
more » ... simultaneous activity of multiple genes, gene networks and cellular pathways. Methodology/Principal Findings: We have constructed genome wide expression profiles from snap frozen post-mortem tissue from the medial temporal lobe of patients with four neurodegenerative disorders (5 AD, 5 PSP, 5 PiD and 5 FTD patients) and 5 control subjects. All patients were matched for age, gender, ApoE-e and MAPT (tau) haplotype. From all groups a total of 790 probes were shown to be differently expressed when compared to control individuals. The results from these experiments were then used to investigate the correlations between clinical, pathological and molecular findings. From the 790 identified probes we extracted a gene set of 166 probes whose expression could discriminate between these disorders and normal ageing. Conclusions/Significance: From genome wide expression profiles we extracted a gene set of 166 probes whose expression could discriminate between neurological disorders and normal ageing. This gene set can be further developed into an accurate microarray-based classification test. Furthermore, from this dataset we extracted a disease specific set of genes and identified two aging related transcription factors (FOXO1A and FOXO3A) as possible drug targets related to neurodegenerative disease.
doi:10.1371/journal.pone.0006826 pmid:19714246 pmcid:PMC2729393 fatcat:gljqkn6cj5hjnlqb427iudpcpe

Profiling transcription initiation in human aged brain using deep-CAGE

Margherita Francescatto, Luba Pardo, Patrizia Rizzu, Morana Vitezic, Javier Simón-Sánchez, Hazuki Takahashi, Carsten Daub, Piero Carninci, Peter Heutink
2011 BMC Bioinformatics  
doi:10.1186/1471-2105-12-s11-a8 pmcid:PMC3277252 fatcat:d42ebbi42fgvteyrkjxeznewc4

Parkinsonian phenotype in Machado-Joseph disease (MJD/SCA3): a two-case report

Conceição Bettencourt, Cristina Santos, Paula Coutinho, Patrizia Rizzu, João Vasconcelos, Teresa Kay, Teresa Cymbron, Mafalda Raposo, Peter Heutink, Manuela Lima
2011 BMC Neurology  
Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder of late onset, which is caused by a CAG repeat expansion in the coding region of the ATXN3 gene. This disease presents clinical heterogeneity, which cannot be completely explained by the size of the repeat tract. MJD presents extrapyramidal motor signs, namely Parkinsonism, more frequently than the other subtypes of autosomal dominant cerebellar ataxias. Although
more » ... m seems to segregate within MJD families, only a few MJD patients develop parkinsonian features and, therefore, the clinical and genetic aspects of these rare presentations remain poorly investigated. The main goal of this work was to describe two MJD patients displaying the parkinsonian triad (tremor, bradykinesia and rigidity), namely on what concerns genetic variation in Parkinson's disease (PD) associated loci (PARK2, LRRK2, PINK1, DJ-1, SNCA, MAPT, APOE, and mtDNA tRNA Gln T4336C). Case presentation: Patient 1 is a 40 year-old female (onset at 30 years of age), initially with a pure parkinsonian phenotype (similar to the phenotype previously reported for her mother). Patient 2 is a 38 year-old male (onset at 33 years of age), presenting an ataxic phenotype with parkinsonian features (not seen either in other affected siblings or in his father). Both patients presented an expanded ATXN3 allele with 72 CAG repeats. No PD mutations were found in the analyzed loci. However, allelic variants previously associated with PD were observed in DJ-1 and APOE genes, for both patients. Conclusions: The present report adds clinical and genetic information on this particular and rare MJD presentation, and raises the hypothesis that DJ-1 and APOE polymorphisms may confer susceptibility to the parkinsonian phenotype in MJD.
doi:10.1186/1471-2377-11-131 pmid:22023810 pmcid:PMC3217914 fatcat:cmjzujyvrrcdzjwulhe7to5f3m

Progranulin mutations in Dutch familial frontotemporal lobar degeneration

Iraad F Bronner, Patrizia Rizzu, Harro Seelaar, Saskia E van Mil, Burcu Anar, Asma Azmani, Laura Donker Kaat, Sonia Rosso, Peter Heutink, John C van Swieten
2007 European Journal of Human Genetics  
Mutations in the progranulin (PGRN) gene have recently been identified in frontotemporal lobar degeneration with ubiquitin inclusions linked to chromosome 17q21. We report here the finding of two novel frameshift mutations and three possible pathogenic missense mutations in the PGRN gene. Furthermore, we determined the frequency of PGRN mutations in familial cases recruited from a large population-based study of frontotemporal lobar degeneration carried out in The Netherlands.
doi:10.1038/sj.ejhg.5201772 pmid:17228326 fatcat:p4d3ibpkdve6tp6dwwnv7uenjm

Comprehensive promoter level expression quantitative trait loci analysis of the human frontal lobe

Cornelis Blauwendraat, Margherita Francescatto, J. Raphael Gibbs, Iris E. Jansen, Javier Simón-Sánchez, Dena G. Hernandez, Allissa A. Dillman, Andrew B. Singleton, Mark R. Cookson, Patrizia Rizzu, Peter Heutink
2016 Genome Medicine  
Expression quantitative trait loci (eQTL) analysis is a powerful method to detect correlations between gene expression and genomic variants and is widely used to interpret the biological mechanism underlying identified genome wide association studies (GWAS) risk loci. Numerous eQTL studies have been performed on different cell types and tissues of which the majority has been based on microarray technology. Methods: We present here an eQTL analysis based on cap analysis gene expression
more » ... (CAGEseq) data created from human postmortem frontal lobe tissue combined with genotypes obtained through genotyping arrays, exome sequencing, and CAGEseq. Using CAGEseq as an expression profiling technique combined with these different genotyping techniques allows measurement of the molecular effect of variants on individual transcription start sites and increases the resolution of eQTL analysis by also including the non-annotated parts of the genome. Results: We identified 2410 eQTLs and show that non-coding transcripts are more likely to contain an eQTL than coding transcripts, in particular antisense transcripts. We provide evidence for how previously identified GWAS loci for schizophrenia (NRGN), Parkinson's disease, and Alzheimer's disease (PARK16 and MAPT loci) could increase the risk for disease at a molecular level. Furthermore, we demonstrate that CAGEseq improves eQTL analysis because variants obtained from CAGEseq are highly enriched for having a functional effect and thus are an efficient method towards the identification of causal variants. Conclusion: Our data contain both coding and non-coding transcripts and has the added value that we have identified eQTLs for variants directly adjacent to TSS. Future eQTL studies would benefit from combining CAGEseq with RNA sequencing for a more complete interpretation of the transcriptome and increased understanding of eQTL signals.
doi:10.1186/s13073-016-0320-1 pmid:27287230 pmcid:PMC4903003 fatcat:wv2fumulujc3pfucucmjpjpizu

Antisense Transcription in Loci Associated to Hereditary Neurodegenerative Diseases

Silvia Zucchelli, FANTOM Consortium, Stefania Fedele, Paolo Vatta, Raffaella Calligaris, Peter Heutink, Patrizia Rizzu, Masayoshi Itoh, Francesca Persichetti, Claudio Santoro, Hideya Kawaji, Timo Lassmann (+4 others)
2019 Molecular Neurobiology  
Natural antisense transcripts are common features of mammalian genes providing additional regulatory layers of gene expression. A comprehensive description of antisense transcription in loci associated to familial neurodegenerative diseases may identify key players in gene regulation and provide tools for manipulating gene expression. We take advantage of the FANTOM5 sequencing datasets that represent the largest collection to date of genome-wide promoter usage in almost 2000 human samples.
more » ... scription start sites (TSSs) are mapped at high resolution by the use of a modified protocol of cap analysis of gene expression (CAGE) for high-throughput single molecule next-generation sequencing with Helicos (hCAGE). Here we present the analysis of antisense transcription at 17 loci associated to hereditary Alzheimer's disease, Frontotemporal Dementia, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease. We focused our analysis on libraries derived from brain tissues and primary cells. We also screened libraries from total blood and blood cell populations in the quest for peripheral biomarkers of neurodegenerative diseases. We identified 63 robust promoters in antisense orientation to genes associated to familial neurodegeneration. When applying a less stringent cutoff, this number increases to over 400. A subset of these promoters represents alternative TSSs for 24 FANTOM5 annotated long noncoding RNA (lncRNA) genes, in antisense orientation to 13 of the loci analyzed here, while the remaining contribute to the expression of additional transcript variants. Intersection with GWAS studies, sample ontology, and dynamic expression reveals association to specific genetic traits as well as cell and tissue types, not limited to neurodegenerative diseases. Antisense transcription was validated for a subset of genes, including those encoding for Microtubule-Associated Protein Tau, α-synuclein, Parkinsonism-associated deglycase DJ-1, and Leucin-Rich Repeat Kinase 2. This work provides evidence for the existence of additional regulatory mechanisms of the expression of neurodegenerative disease-causing genes by previously not-annotated and/or not-validated antisense long noncoding RNAs.
doi:10.1007/s12035-018-1465-2 pmid:30610612 pmcid:PMC6614138 fatcat:4h7mmrh5mrhazlykyvbf6nifiq

Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation

Merel O. Mol, Jeroen G.J. van Rooij, Esther Brusse, Annemieke J.M.H. Verkerk, Shamiram Melhem, Wilfred F.A. den Dunnen, Patrizia Rizzu, Chiara Cupidi, John C. van Swieten, Laura Donker Kaat
2020 Neurology: Genetics  
Rizzu, MD, PhD German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany Analyzed and interpreted the data and revised the manuscript Chiara Cupidi, MD, PhD IRCCS Centro Neurolesi "Bonino  ...  , Rotterdam, the Netherlands Performed laboratory work Wilfred F.A. den Dunnen, MD, PhD University Medical Centre Groningen, Groningen, the Netherlands Interpreted the data and revised the manuscript Patrizia  ... 
doi:10.1212/nxg.0000000000000417 pmid:32337344 pmcid:PMC7164971 fatcat:q5ubl5dlzzhxdd2tr6meldmbgm

Drosophila DJ-1 Mutants Are Selectively Sensitive to Environmental Toxins Associated with Parkinson's Disease

Marc Meulener, Alexander J. Whitworth, Cecilia E. Armstrong-Gold, Patrizia Rizzu, Peter Heutink, Paul D. Wes, Leo J. Pallanck, Nancy M. Bonini
2005 Current Biology  
Parkinson's disease (PD) is a common neurodegenerative disorder that displays both sporadic and inherited forms [1] . Exposure to several common environmental toxins acting through oxidative stress has been shown to be associated with PD [2]. One recently identified inherited PD gene, DJ-1, may have a role in protection from oxidative stress [3-10], thus potentially linking a genetic cause with critical environmental risk factors. To develop an animal model that would allow integrative study of
more » ... genetic and environmental influences, we have generated Drosophila lacking DJ-1 function. Fly DJ-1 homologs exhibit differential expression: DJ-1␤ is ubiquitous, while DJ-1␣ is predominantly expressed in the male germline. DJ-1a and DJ-1b double knockout flies are viable, fertile, and have a normal lifespan; however, they display a striking selective sensitivity to those environmental agents, including paraquat and rotenone, linked to PD in humans. This sensitivity results primarily from loss of DJ-1␤ protein, which also becomes modified upon oxidative stress. These studies demonstrate that fly DJ-1 activity is selectively involved in protection from environmental oxidative insult in vivo and that the DJ-1␤ protein is biochemically responsive to oxidative stress. Study of these flies will provide insight into the critical interplay of genetics and environment in PD. Results Mutation of DJ-1 Homologs in Drosophila DJ-1 proteins are evolutionarily conserved throughout organisms ranging from vertebrates to yeast and bac-*Correspondence: nbonini@sas.upenn.edu 6 These authors contributed equally to this work.
doi:10.1016/j.cub.2005.07.064 pmid:16139213 fatcat:dcushe4tlrahjfxfit33s226rm

Trehalose Improves Human Fibroblast Deficits in a New CHIP-Mutation Related Ataxia

Maria Jose Casarejos, Juan Perucho, Jose Luis López-Sendón, Justo García de Yébenes, Conceição Bettencourt, Ana Gómez, Carolina Ruiz, Peter Heutink, Patrizia Rizzu, Maria Angeles Mena, David R. Borchelt
2014 PLoS ONE  
In this work we investigate the role of CHIP in a new CHIP-mutation related ataxia and the therapeutic potential of trehalose. The patient's fibroblasts with a new form of hereditary ataxia, related to STUB1 gene (CHIP) mutations, and three age and sex-matched controls were treated with epoxomicin and trehalose. The effects on cell death, protein misfolding and proteostasis were evaluated. Recent studies have revealed that mutations in STUB-1 gene lead to a growing list of molecular defects as
more » ... eregulation of protein quality, inhibition of proteasome, cell death, decreased autophagy and alteration in CHIP and HSP70 levels. In this CHIP-mutant patient fibroblasts the inhibition of proteasome with epoxomicin induced severe pathophysiological age-associated changes, cell death and protein ubiquitination. Additionally, treatment with epoxomicin produced a dose-dependent increase in the number of cleaved caspase-3 positive cells. However, cotreatment with trehalose, a disaccharide of glucose present in a wide variety of organisms and known as a autophagy enhancer, reduced these pathological events. Trehalose application also increased CHIP and HSP70 expression and GSH free radical levels. Furthermore, trehalose augmented macro and chaperone mediated autophagy (CMA), rising the levels of LC3, LAMP2, CD63 and increasing the expression of Beclin-1 and Atg5-Atg12. Trehalose treatment in addition increased the percentage of immunoreactive cells to HSC70 and LAMP2 and reduced the autophagic substrate, p62. Although this is an individual case based on only one patient and the statistical comparisons are not valid between controls and patient, the low variability among controls and the obvious differences with this patient allow us to conclude that trehalose, through its autophagy activation capacity, anti-aggregation properties, anti-oxidative effects and lack of toxicity, could be very promising for the treatment of CHIP-mutation related ataxia, and possibly a wide spectrum of neurodegenerative disorders related to protein disconformation.
doi:10.1371/journal.pone.0106931 pmid:25259530 pmcid:PMC4178022 fatcat:7erfjz5g2jb2rkb7ugdnbzardq

A Double RING-H2 Domain in RNF32, a Gene Expressed during Sperm Formation

Marijke J. van Baren, Herma C. van der Linde, Guido J. Breedveld, Willy M. Baarends, Patrizia Rizzu, Esther de Graaff, Ben A. Oostra, Peter Heutink
2002 Biochemical and Biophysical Research Communications - BBRC  
The RING domain is a cysteine-rich zinc-binding motif, which is found in a wide variety of proteins, among which are several proto-oncogenes and the gene implicated in autosomal recessive juvenile parkinsonism, Parkin. The domain mediates binding to other proteins, either via their RING domains or other motifs. In several proteins, RING domains are found in combination with other cysteine-rich binding motifs and some proteins contain two RING domains. Recent evidence suggests that RING finger
more » ... oteins function in the ubiquitin pathway as E3 ligases. A variant of the RING domain is the RING-H2 domain, in which one of the cysteines is replaced by a histidine. We have cloned and characterized a novel gene, RNF32, located on chromosome 7q36. RNF32 is contained in 37 kb of genomic DNA and consists of 9 constitutive and 8 alternatively spliced exons, most of which are alternative first exons. A long and a short transcript of the gene are expressed; the short transcript containing exons 1-4 only. This gene encodes two RING-H2 domains separated by an IQ domain of unknown function. This is the first reported gene with a double RING-H2 domain. In humans, RNF32 overlaps with a processed retroposon located on the opposite strand, C7orf13. RNF32 is specifically expressed in testis and ovary, whereas C7orf13 is testis-specific, suggesting that its expression may be regulated by elements in the RNF32 promoter region. RNF32 is expressed during spermatogenesis, most likely in spermatocytes and/or in spermatids, suggesting a possible role in sperm formation. © 2002 Elsevier Science (USA)
doi:10.1006/bbrc.2002.6612 pmid:11890671 fatcat:zn24sofjsvf55nmy4r3o7kwu3i

Resequencing Three Candidate Genes for Major Depressive Disorder in a Dutch Cohort

Eva C. Verbeek, Marianna R. Bevova, Zoltán Bochdanovits, Patrizia Rizzu, Ingrid M. C. Bakker, Tiny Uithuisje, Eco J. De Geus, Johannes H. Smit, Brenda W. Penninx, Dorret I. Boomsma, Witte J. G. Hoogendijk, Peter Heutink (+1 others)
2013 PLoS ONE  
Major depressive disorder (MDD) is a psychiatric disorder, characterized by periods of low mood of more than two weeks, loss of interest in normally enjoyable activities and behavioral changes. MDD is a complex disorder and does not have a single genetic cause. In 2009 a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. Many of the top signals of this GWAS mapped to a region spanning the gene PCLO, and the non-synonymous coding single nucleotide polymorphism (SNP)
more » ... rs2522833 in the PCLO gene became genome wide significant after post-hoc analysis. We performed resequencing of PCLO, GRM7, and SLC6A4 in 50 control samples from the GAIN-MDD cohort, to detect new genomic variants. Subsequently, we genotyped these variants in the entire GAIN-MDD cohort and performed association analysis to investigate if rs2522833 is the causal variant or simply in linkage disequilibrium with a more associated variant. GRM7 and SLC6A4 are both candidate genes for MDD from literature. We aimed to gather more evidence that rs2522833 is indeed the causal variant in the GAIN-MDD cohort or to find a previously undetected common variant in either PCLO, GRM7, or SLC6A4 with a higher association in this cohort. After next generation sequencing and association analysis we excluded the possibility of an undetected common variant to be more associated. For neither PCLO nor GRM7 we found a more associated variant. For SLC6A4, we found a new SNP that showed a lower P-value (P = 0.07) than in the GAIN-MDD GWAS (P = 0.09). However, no evidence for genome-wide significance was found. Although we did not take into account rare variants, we conclude that our results provide further support for the hypothesis that the non-synonymous coding SNP rs2522833 in the PCLO gene is indeed likely to be the causal variant in the GAIN-MDD cohort.
doi:10.1371/journal.pone.0079921 pmid:24278217 pmcid:PMC3836783 fatcat:op3y3vudyzhhppxvfl3pg7267a

The ΔK280 Mutation in MAP tau Favors Exon 10 Skipping In Vivo

John C. van Swieten, Iraad F. Bronner, Asma Azmani, Lies-Anne Severijnen, Wouter Kamphorst, Rivka Ravid, Patrizia Rizzu, Rob Willemsen, Peter Heutink
2007 Journal of Neuropathology and Experimental Neurology  
Tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 are associated with changes in alternative splicing of exon 10. The $K280 mutation in exon 10 is exceptional because in vitro observations suggest a dramatic effect on microtubule binding, enhanced self-aggregation, as well as a decrease of the 4R/3R ratio by the ablation of an exon splicing enhancer element. Using immunohistochemistry, Western blotting, and electron microscopy on brain material with the $K280
more » ... tion, we investigated which of these effects is most dominant in vivo. The brain showed abundant Pick bodies in several brain regions, which stained positive with 3-repeat-specific but not with 4-repeat-specific tau antibodies. Western blots of sarkosyl-insoluble tau showed exclusively three repeat (3R0N and 3R1N) tau in most regions, although some 4R1N could be detected in the frontal cortex. In addition, the sarkosyl-soluble tau fraction showed a significantly higher amount of 3-repeat tau. Because quantitative analysis of 4R and 3R mRNA transcripts showed a 4R/3R ratio of only 0.3, association between increased transcription and protein expression was observed. These observations confirm the postulated hypothesis that the $K280 mutation abolishes a splice enhancer element, which overrules the decreased microtubule binding and enhanced self-aggregation.
doi:10.1097/nen.0b013e31802c39a4 pmid:17204933 fatcat:vkehr6lq35eu7parhzqi2ktb24

Proteomic and Functional Analyses Reveal a Mitochondrial Dysfunction in P301L Tau Transgenic Mice

Della C. David, Susanne Hauptmann, Isabel Scherping, Katrin Schuessel, Uta Keil, Patrizia Rizzu, Rivka Ravid, Stefan Dröse, Ulrich Brandt, Walter E. Müller, Anne Eckert, Jürgen Götz
2005 Journal of Biological Chemistry  
Transgenic mice overexpressing the P301L mutant human tau protein exhibit an accumulation of hyperphosphorylated tau and develop neurofibrillary tangles. The consequences of tau pathology were investigated here by proteomics followed by functional analysis. Mainly metabolism-related proteins including mitochondrial respiratory chain complex components, antioxidant enzymes, and synaptic proteins were identified as modified in the proteome pattern of P301L tau mice. Significantly, the reduction
more » ... mitochondrial complex V levels in the P301L tau mice revealed using proteomics was also confirmed as decreased in human P301L FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) brains. Functional analysis demonstrated a mitochondrial dysfunction in P301L tau mice together with reduced NADH-ubiquinone oxidoreductase activity and, with age, impaired mitochondrial respiration and ATP synthesis. Mitochondrial dys-function was associated with higher levels of reactive oxygen species in aged transgenic mice. Increased tau pathology as in aged homozygous P301L tau mice revealed modified lipid peroxidation levels and the up-regulation of antioxidant enzymes in response to oxidative stress. Furthermore, P301L tau mitochondria displayed increased vulnerability toward beta-amyloid (Abeta) peptide insult, suggesting a synergistic action of tau and Abeta pathology on the mitochondria. Taken together, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by Abeta.
doi:10.1074/jbc.m500356200 pmid:15831501 fatcat:piw3gnjlyvcrpeniq5kn7wkjyy

Genetic Influences on Thought Problems in 7-Year-Olds: A Twin-Study of Genetic, Environmental and Rater Effects

Abdel Abdellaoui, Meike Bartels, James J. Hudziak, Patrizia Rizzu, Toos CEM van Beijsterveldt, Dorret I. Boomsma
2008 Twin Research and Human Genetics  
AbstractThe Thought–Problem scale (TP) of the CBCL assesses symptoms such as hallucinations and strange thoughts/behaviors and has been associated with other behavioral disorders. This study uses parental reports to examine the etiology of variation in TP, about which relatively little is known, in 7-year-old twins. Parental ratings on TP were collected in 8,962 7-year-old twin pairs. Because the distribution of TP scores was highly skewed scores were categorized into 3 classes. The data were
more » ... alyzed under a threshold liability model with genetic structural equation modeling. Ratings from both parents were simultaneously analyzed to determine the rater agreement phenotype (or common phenotype [TPc]) and the rater specific phenotype [TPs] that represents rater disagreement caused by rater bias, measurement error and/or a unique view of the parents on the child's behavior. Scores on the TP-scale varied as a function of rater (fathers rated fewer problems), sex (boys scored higher) and zygosity (DZ twins scored higher). The TPc explained 67% of the total variance in the parental ratings. Variation in TPc was influenced mainly by the children's genotype (76%). Variance in TPs also showed a contribution of genetic factors (maternal reports: 61%, paternal reports: 65%), indicating that TPs does not only represent rater bias. Shared environmental influences were only found in the TPs. No sex differences in genetic architecture were observed. These results indicate an important contribution of genetic factors to thought problems in children as young as 7 years.
doi:10.1375/twin.11.6.571 pmid:19016612 fatcat:xpsnywqwi5ejflrbpdpe2vam6u

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

Cornelis Blauwendraat, Carlo Wilke, Javier Simón-Sánchez, Iris E Jansen, Anika Reifschneider, Anja Capell, Christian Haass, Melissa Castillo-Lizardo, Saskia Biskup, Walter Maetzler, Patrizia Rizzu, Peter Heutink (+1 others)
2017 Genetics in Medicine  
Purpose: To define the genetic spectrum and relative gene frequencies underlying clinical frontotemporal dementia (FTD). Methods: We investigated the frequencies and mutations in neurodegenerative disease genes in 121 consecutive FTD subjects using an unbiased, combined sequencing approach, complemented by cerebrospinal fluid Aβ 1-42 and serum progranulin measurements. Subjects were screened for C9orf72 repeat expansions, GRN and MAPT mutations, and, if negative, mutations in other
more » ... tive disease genes, by whole-exome sequencing (WES) (n = 108), including WES-based copy-number variant (CNV) analysis. Results: Pathogenic and likely pathogenic mutations were identified in 19% of the subjects, including mutations in C9orf72 (n = 8), GRN (n = 7, one 11-exon macro-deletion) and, more rarely, CHCHD10, TARDBP, SQSTM1 and UBQLN2 (each n = 1), but not in MAPT or TBK1. WES also unraveled pathogenic mutations in genes not commonly linked to FTD, including mutations in Alzheimer (PSEN1, PSEN2), lysosomal (CTSF, 7-exon macro-deletion) and cholesterol homeostasis pathways (CYP27A1). Conclusion: Our unbiased approach reveals a wide genetic spectrum underlying clinical FTD, including 11% of seemingly sporadic FTD. It unravels several mutations and CNVs in genes and pathways hitherto not linked to FTD. This suggests that clinical FTD might be the converging downstream result of a delicate susceptibility of frontotemporal brain networks to insults in various pathways.
doi:10.1038/gim.2017.102 pmid:28749476 pmcid:PMC5846812 fatcat:lsmiivzozffyflsziulb3nwmrm
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