Hintergrund: Der Insulin-like growth factor receptor (IGF1R) spielt eine zentrale Rolle bei Wachstumsprozessen. Heterozygote IGF1R-Mutationen führen durch eine partielle IGF1-Resistenz zu Kleinwuchs. Methoden: Auxologische und endokrinologische Daten des Patienten wurden erhoben. Anhand von Fibroblasten wurde die IGF1R-Deletion charakterisiert und die Auswirkungen auf die mRNA- und Protein-Expression sowie die Signaltransduktion untersucht. Ergebnisse: Der Junge, der eine heterozygote Exon 6 Deletion im IGF1R – durch Alu-Rekombination verursacht – und eine heterozygote SHOX-Variante (p.Met240Ile) in seinem Genom vereint, kam ‚appropriate for gestational age‘ zur Welt, entwickelte aber postnatal eine Wachstumsretardierung. Die Endokrinologischen Daten waren unauffällig. Der Patient zeigt keine Stigmata, die bei anderen IGF1- oder SHOX-Mutationsträgern beschrieben wurden. Durch Nonsense-Mediated mRNA Decay kommt es zu einer Dosisreduktion der IGF1-Rezeptoren und einer entsprechenden verminderten Aktivierung der Rezeptoren, nicht aber des Signalwegs. Zusammenfassung: Der Patient trägt eine bisher unbeschrieben heterozygote IGF1R-Deletion, die zu Kleinwuchs führt. Ursächlich dafür ist eine durch die Mutation verursachte Dosisreduktion der IGF1-Rezeptoren.:Inhaltsverzeichnis I Abkürzungsverzeichnis - 4 - 1 Bibliographische Beschreibung - 7 - 1.1 Referat - 7 - 2 Einleitung und Hintergrund - 9 - 2.1 Das menschliche Wachstum - 9 - 2.2 Das IGF-System als Regulator von Wachstum u. Entwicklung - 10 - 2.3 Der IGF1-Rezeptor - 11 - 2.4 Formen des Kleinwuchses - 12 - 2.5 IGF1R-Mutationen - 13 - 2.6 SHOX-Defizienz - 14 - 2.7 Der Nonsense-Mediated mRNA Decay - 15 - 2.8 Alu-Elemente - 16 - 2.9 Überleitung - 17 - 4 Originalpublikation - 18 - 5 Zusammenfassung der Arbeit - 31 - 5.1 Patientenbeschreibung - 32 - 5.2 Experimentelle Untersuchungen - 33 - 5.3 Interpretation - 35 - 5.4 Ausblick - 37 - 6 Literaturverzeichnis - 39 - III Curriculum vitae - 50 - IV Danksagung - 52 -

Doctor of Education / Department of Special Education, Counseling and Student Affairs / James Teagarden / This study investigated the effectiveness of an early literacy program for first grade students classified as at-risk for emotional and behavioral disorders, who were nonresponsive to previous schoolwide interventions, and who performed in the bottom one-third of their class on a standardized reading assessment. This study, which consisted of a multiple-probe across intervention groups experimental design aimed to produce literacy and behavior results previously obtained by other well-known researchers. Results indicated growth in oral reading fluency for all five participants, in nonsense word fluency for four out of the five participants, and a decreased display of total disruptive behaviors for all. Findings reaffirm outcomes obtained in previous investigations; specifically, improved early literacy skills are concomitant with ongoing decreases in disruptive classroom behavior. Limitations are discussed and suggestions for future research are provided.

The aim of this thesis was to identify genetic factors involved in frontotemporal lobar degeneration (FTLD), a neurodegenerative disorder clinically characterised by a progressive change in personality, behaviour and language. FTLD is a genetically complex disorder and a positive family history is found in up to 40% of the cases. In 10-20% of the familial cases the disease can be explained by mutations in the gene encoding the microtubule associated protein tau (MAPT). In the first study we describe the clinical and neuropathological features of a Finnish family with FTLD caused by a mutation in MAPT. We also provide evidence that the pathogenic mechanism of this mutation is through altered splicing of MAPT transcripts. Recently, mutations in the gene encoding progranulin (PGRN) were identified as a major cause of FTLD. In the second study we describe a Swedish family with FTLD caused by a frameshift mutation in PGRN. We provide a clinical and neuropathological description of the family, as well as evidence that the pathogenicity of this mutation is through nonsense-mediated decay of the mutant mRNA transcripts and PGRN haploinsufficiency. In the third study we describe a novel PGRN splice site mutation and a previously described PGRN frameshift mutation, found in a mutation screen of 51 FTLD patients. We describe the clinical and neuropathological characteristics of the mutation carriers and demonstrate that haploinsufficiency is the pathogenic mechanism of the two mutations. In the fourth study we investigate the prevalence of PGRN and MAPT gene dosage alterations in 39 patients with FTLD. No gene dosage alterations were identified, indicating that variations in copy number of the PGRN and MAPT genes are not a common cause of disease, at least not in this FTLD patient collection.

Le NMD (nonsense-mediated mRNA decay) est un mécanisme qui reconnaît et dégrade les ARNm portant un codon stop prématuré afin d’empêcher la synthèse de protéines tronquées qui pourraient avoir des effets néfastes pour la cellule ou tout simplement être non fonctionnelles. Cependant, dans un certain nombre de cas, selon la position du codon stop prématuré, la protéine tronquée qui serait synthétisée si le NMD n’existait pas, pourrait remplir complètement ou partiellement la fonction de la protéine sauvage. Il faut noter qu’un codon stop prématuré est retrouvé dans le gène responsable d’une pathologie dans un tiers des maladies génétiques et de nombreuses formes de cancer. Dans la plus grande majorité des cas, la maladie se développe non pas parce qu’une protéine tronquée non fonctionnelle ou instable est synthétisée, mais plutôt parce que le gène muté n’est pas exprimé du fait de l’intervention du NMD sur l’ARNm qui en dérive. Une nouvelle approche thérapeutique de ces maladies serait d’inhiber le NMD afin de permettre la synthèse de protéines tronquées fonctionnelles et sauver le phénotype clinique. Nous avons donc décidé de rechercher des inhibiteurs du mécanisme du NMD parmi des petites molécules chimiques. Pour cela, nous avons mis au point un système de criblage en culture cellulaire reliant l’efficacité du NMD dans une cellule avec une activité luciférase mesurable directement sur les cultures cellulaires, au moyen d’un luminomètre. A partir d’un premier criblage d’environ 1500 composés chimiques, nous avons identifié une nouvelle molécule capable d’inhiber efficacement le NMD. De façon intéressante, cette nouvelle molécule est capable également d’induire la synthèse de protéines entières à partir d’un ARNm portant un codon stop prématuré. Nous avons utilisé cet inhibiteur dans des expériences pour déterminer son potentiel thérapeutique sur des modèles cellulaires de maladies génétiques tels que la dystrophie musculaire de Duchenne, la mucoviscidose et le cancer. Nos résultats démontrent que l’inhibition du NMD peut être en effet envisagée comme une nouvelle approche thérapeutique pour des maladies causées par l’apparition d’une mutation non sens. Nous avons aussi identifié une autre molécule chimique capable d’inhiber le NMD et permettant de faire un lien entre efficacité du NMD et intégrité du cytosquelette. / MRNAs harboring a premature termination codon are rapidly degraded by a mechanism called nonsense-mediated mRNA decay (NMD). NMD is a surveillance pathway that prevents the synthesis of truncated proteins that could be harmful for the cell or simply be non-functional. However in some cases, depending on the position of the premature stop codon, the truncated protein that would be synthesized if there were no NMD would be partially or fully as functional as the wild-type protein. It is noteworthy that premature termination codons are found in approximately one-third of inherited genetic disorders and several forms of cancer. In most of cases the disease arises not because a non-functional or unstable truncated protein is synthesized, but instead because the degradation of the transcript by NMD leads to complete loss of protein production. Therefore, NMD inhibition could be an interesting therapeutic approach in some cases of nonsense-related genetic diseases in which functional truncated proteins can restore the clinical phenotype. We decided to search for NMD inhibitors among thousands of small molecules. We developed a cell-based screening method which couples NMD efficiency into the cell to a luciferase activity that can be measured directly into cells by a luminometer. From a screening of approximately 1500 compounds, we have identified one molecule capable of efficiently inhibit NMD. Interestingly, this compound is also able to induce the synthesis of full-length proteins from an mRNA bearing a premature termination codon. We evaluated the therapeutic potential of this compound in different cellular models of genetic disorders such as Duchenne’s muscular dystrophy, cystic fibrosis and cancer. Our results demonstrate that NMD inhibition in general can be considered as an useful therapeutic approach to rescue PTC consequences in genetic diseases provoked by the apparition of a nonsense mutation. We have also identified another compound that inhibits NMD and uncovers a relationship between the NMD efficiency and the integrity of the cytoskeleton.

Nonsense mediated mRNA decay (NMD) is a surveillance mechanism that targets transcripts containing premature stop codons (PTCs) for degradation, and that also regulates up to 10% of the whole transcriptome. During the course of my PhD I set out to identify novel NMD factors by performing a genome-wide RNA interference (RNAi) screen in a transgenic strain of Caenorhabditis elegans carrying an NMD reporter. I identified five novel proteins that are putative NMD factors in worms: NGP-1, NPP-20, AEX-6, PBS-2 and NOAH-2. Knock-down of these proteins led to severe developmental defects: worms were either arrested during various larval stages or died prematurely. The only exception was AEX-6, the knockdown of which led to a milder phenotype. Homology analysis of the novel C. elegans NMD factors showed that these proteins are conserved in human, with the exception of NOAH-2, which only has a homologue in Drosophila melanogaster, NOMPA. By performing an NMD assay in human cells, I demonstrated that GNL2 (NGP-1) and SEC13 (NPP-20) are functionally conserved NMD factors in human. Analysis of the consequences of depletion of GNL2, SEC13, UPF1 or UPF2 on the transcriptome of HeLa cells revealed that these four proteins co-regulate a subset of endogenous NMD targets, whilst also independently regulating the expression of other sets of transcripts. The findings presented in this thesis further our knowledge of the biology of NMD in both nematodes and humans. They demonstrate the existence of further regulators of this surveillance pathway, and add a layer of complexity to this fine-tuned biological process.

Murilo Rubião é visto como um caso raro na literatura brasileira: poucos autores produziram como ele uma ficção tão decididamente marcada por situações insólitas, eventos estranhos, cenas inusitadas. Não à toa, sua literatura é estudada a partir de discussões em torno do chamado fantástico contemporâneo (ou neofantástico, ou realismo fantástico, ou realismo mágico, ou realismo maravilhoso). Por agora, no entanto, a questão é outra: alguns engenhos em Rubião potencializam um horizonte de pensamento que promove reflexões sobre a noção de não-senso (não-significado). O não-senso é uma possibilidade, por assim dizer, transgenérica - ainda que por vezes possa ser decidido em melhores circunstâncias no que se convencionou chamar, genericamente, literatura nonsense, literatura do absurdo e mesmo literatura fantástica. A fim de fazer jus a este horizonte, esta dissertação cruza os contos, animada por uma lógica do acontecimento, buscada fora das tradições platônicas e aristotélicas, criando ao longo dos capítulos cenários e instâncias associativas que, por sua vez, solicitam algumas distinções: explicação laboratorial e experiência lógica, senso-significado e senso-sentido, imagem e imagem pura, ser e extra-ser. A discussão aqui travada visa contribuir para a prática de uma experiência na literatura de Rubião. / Murilo Rubião is seen as a rare case in Brazilian literature: few authors have produced a fiction so strongly marked by unusual situations, strange events, and unusual scenes. Not for nothing, his literature is studied starting by discussions on the so-called contemporary fantastic (or neo-fantastic, or fantastic realism, or magic realism, or marvelous realism). For now, however, the question is another one: some of Rubiãos pyrotechnics empower a horizon of thought that promotes reflections on the notion of nonsense (non-meaning). The nonsense is, so to speak, a transgender possibility - though sometimes it can be determined, in the best circumstances, in what is generically called nonsense literature, literature of the absurd, and even fantastic literature. In order to make justice to this horizon, this dissertation travels the tales, it animated by a logic of the event, outside of the Platonic and Aristotelian traditions, creating, throughout the chapters, sceneries and associative instances which, in turn, ask for some distinctions: laboratorial explanation and logic experience, sense-meaning and sense-sense, image and pure image, being and extra-being. The discussion promoted here aims to contribute to the practice of an experience in the literature of Rubião.

A presente tese se ocupa de uma vertente da literatura e do cinema contemporâneos, especialmente do escritor Julio Cortázar e do cineasta David Lynch, que: busca um novo tratamento para a realidade, não esconde os artifícios discursivos das obras, joga com estratégias ilusionistas e antiilusionistas, debate a própria ficção por meio de recursos metaficcionais, que se utiliza da metáfora do teatro como espaço diferenciado e como palco de ilusões e que trabalha com a questão do fantástico (ou absurdo). Grande parte do trabalho é dedicada ao estudo da obra do escritor argentino Julio Cortázar. Estudo esse que se constrói a partir das correspondências entre as produções ficcionais e teóricas de Cortázar, além de suas próprias entrevistas. Cortázar é nosso foco principal e dele, acreditamos, brotou um veio dos mais significativos na narrativa contemporânea, que estabelece novos modos de se lidar com a representação e com as referências. É devido a esses aspectos, apontados anteriormente, que estabelecemos relações com outros autores, inclusive do cinema, como é o caso de David Lynch / This thesis deals with one aspect of literature and contemporary cinema, especially the writer Julio Cortázar and filmmaker David Lynch, that: a search for new treatment really does not hide the artifice of the discursive works, plays with illusionist and anti-illusionist strategies, debate the fiction itself through metaficcionais resources, which uses the metaphor of the theater as a space variable and to stage illusions and working with the issue of the fantastic (or nonsense). Much of the work is devoted to the study of the work of Argentine writer Julio Cortázar. Study which is constructed from the correspondence between the fictional and theoretical productions of Cortázar, and his own interviews. Cortázar is our main focus and goals, we came a shaft of the most significant in contemporary novels, establishing new ways of dealing with the representation and referrals. It is because of these issues, previously mentioned, we have established relationships with other authors, including the cinema, as is the case of David Lynch

Nonsense-mediated mRNA decay (NMD) is an important protective mechanism to guard against erroneous transcripts particularly mRNA transcripts containing premature termination codons (PTC). In classical teaching, such erroneous transcripts (called nonsense-mediated decay targeted RNA, nt-RNA here) are considered as incidental non-specific side-products of the cellular transcription machinery and they are rapidly cleared by NMD and thus they exists in scanty quantity inside a cell (i.e. at a very low steady state abundance). As a side product of stochastic transcriptional error, they are also commonly considered to carry no biologic function. / By analysis of a large collection of RNA-seq data in TCGA (over 4000 samples and the hard disk storage was over 50 TB), it was found that nt-RNA were produced in large amount for some genes, sometimes, they were even more abundant than the normal transcripts of the corresponding genes. / Based on the hypothesis that some nt-RNA are specifically produced by a biological process (in contrast to a process happened by chance), the aims of this work are: 1) To quantify the expression of nt-RNA (survey of the spectrum); 2) To examine the relationship between nt-RNA and protein expression (biological roles); 3) To detect nt-RNAs that affect prognosis of cancer (biological roles); 4) To apply nt-RNA as diagnostic biomarkers for cancer (application); 5) To identify nt-RNAs to classify tumors for unknown primary (CUP, application). / Firstly, nt-RNA were defined from Gene databases and all PTC containing transcripts were compared to their corresponding normal transcripts to locate specific signature tags (both short segments of sequences and splice junctions) for each of the nt-RNA. And the presence and counts of these nt-RNA signature tag were searched in all RNA reads of RNA-seq datasets. Such search and counting produced the read counts of each nt-RNA signature tag and all RNA-read containing such tags are targets for NMD. RNA-seq datasets used in this study included TCGA normal samples, TCGA tumor samples and cancer cell lines for 13 cancer types. / In the example of KIRC, it was found that most differentially expressed nt-RNA (tumor vs control) were related to differential expression of the corresponding normal transcripts. However, nt-RNA were produced in 900 genes which were independent of higher production of the normal transcripts. In the example of KIRC, collection of 12 genes in the proteasome ubiquitination pathway standed out among the highly produced nt-RNA. This finding is very interesting as VHL-HIF1A is a key oncogenesis mechanism in KIRC and normal HIF1A degradation required proteasomal ubiquitination pathway. GO analysis was highly significant at p-value<4.11E-05. And the nt-RNA producing genes included PSMB4, PSMD14, PSMC6, PSMD13, PSMB1, VCP, ANAPC5, PSMA4, PSMD3, ANAPC7, OS9, GCLC. / Secondly, some nt-RNA retarded translation of the normal transcripts. By using proteome data, the relationship between quantity of nt-RNA unique tags and normal protein product were analyzed by ANOVA comparison of linear models. It was found that 422 nt-RNA unique tags influenced the expression of proteins, which suggested a potential biological action of these nt-RNA. PTEN also produced nt-RNA in KIRC and tumor cells with higher PTEN nt-RNA had a lower PTEN protein level (p-value of ANOVA comparison of linear models: 0.017). Survival analysis results showed that PTEN nt-RNA levels affected survival, which suggested that it can be used as biomarker for prognosis. Furthermore, survival analysis were done for other nt-RNA unique tags which affected protein expression using clinical data. / Thirdly, the application of nt-RNA as diagnostic markers and markers to define tumor origin in CUP were examined. nt-RNA were identified in different types of tumors. Here, only nt-RNA that were independent of the normal gene transcripts in term of differential expression were used as biomarkers. By comparing tumor samples with normal samples, nt-RNAs as diagnostic markers were detected. Unsupervised clustering was performed for these nt-RNAs and heat maps showed high degree of separation of tumor and normal samples. For studying tumor origin in CUP, in both cross-validation study in the training dataset (N=541) and independent sample set external validation (N=2462), a highly discriminating sets of nt-RNAs were defined for most cancers examined (400 nt-RNA seq. tags). Unsupervised clustering was performed for the 400 nt-RNA seq. tags and heat maps showed its power to define tumor origin in CUP. And then the significance of classifier formed by 400 nt-RNA seq. tags was measured by performing 100 resampling of the training set. The results for the 100 resampling showed that the correctly classified instance rate for training set had 96.4895% ± 0.75% (mean ± standard deviation); for validation set had 91.0239% ± 1.032611%. / In conclusion, this study showed nt-RNA can have important biological function and be used for various applications. It’s a potential biomarker for diagnosis and prognosis of diseases. And it can also be used to decide the origin site of tumors, which indicates that nt-RNA will provide great information for potential application in diagnosis of cancer and determining the origin in cancer of unknown primary site (CUP). [With diagram] / 無意介導的mRNA降解（NMD）是一種重要的保護機制，它可以防止錯誤的轉錄本，特別是含有提前終止密碼子的轉錄本。在經典的教學里，這種錯誤的轉錄本（這裡稱為無意介導的mRNA降解所靶向的轉錄本，記為nt-RNA）被認為是細胞轉錄過程中偶然產生的非特異性的副產物，它們很快被NMD清除，因此它們在細胞內的表達很少（即穩態時它們的表達量很少）。作為隨機的轉錄錯誤的一個副產物，它們通常被認為是沒有生物功能的。 / 通過分析大量的來自TCGA的RNA-seq的數據（超過4000個樣本，存儲空間超過50TB），我們發現一些基因的nt-RNA有很高的表達量，有的甚至超過同一個基因的正常轉錄本的表達量。 / 我們的假設是一些nt-RNA是由某個生物過程特定產生的，而不是偶然產生的。基於這一假設，本研究的目標有：（1）量化nt-RNA的表達（表達譜的調查）；（2）探索nt-RNA與蛋白質表達的關係（生物功能）；（3）尋找可以影響癌症預後的nt-RNA（生物功能）；（4）用nt-RNA作為癌症診斷的生物標記物（應用）；（5）識別可以用來區分原发灶不明的癌症的nt-RNA（應用）。 / 首先，通過基因的數據庫定義nt-RNA，并將這些nt-RNA與相應的正常的轉錄本進行比較，找到每個nt-RNA特有的標簽（包括系列的片段和剪接位点）。進而在RNA-seq數據所有的讀段中搜索這些nt-RNA特有的標簽并記數。通過這樣的搜索和記數，產生了每個nt-RNA特有標簽的讀段數目，而包含這些標簽的讀段就是NMD的靶標。本研究中使用的RNA-seq數據包含13種癌症的TCGA正常和癌症樣本，以及癌細胞系的樣本數據。 / 在腎癌的例子中，大多數差異表達（癌症與正常比較）的nt-RNA和它相應的正常的轉錄本的差異表達是有關聯的。然而，900个基因產生的nt-RNA與正常轉錄本的高表達是獨立的。我們發現與白酶體泛素化通路相關的12個基因高表達nt-RNA。這個發現是很有意思的，因為VHL-HIF1A是KIRC的一個重要的致癌機制，而正常的HIF1A的降解需要通過白酶體泛素化通路。白酶體泛素化通路在基因富集分析中是顯著的（p值<4.11E-05）。這12個基因分別是PSMB4，PSMD14，PSMC6，PSMD13，PSMB1，VCP，ANAPC5，PSMA4，PSMD3，ANAPC7，OS9，GCLC。 / 其次，一些nt-RNA可以降低正常轉錄本的翻譯。利用蛋白組數據，我們用ANOVA比較線性模型的方法研究了nt-RNA特有的標簽與正常的蛋白產物的關係。結果發現，422个nt-RNA特有的標簽影響蛋白質的表達，這說明nt-RNA具有潛在的生物作用。PTEN也在KIRC裡產生nt-RNA，PTEN的nt-RNA表達越高的樣本，含有越少的PTEN蛋白產物（ANOVA比較線性模型的p值=0.017）。生存分析的結果顯示PTEN的nt-RNA影響生存率，這說明PTEN的nt-RNA可以作為癌症預後的生物標記物。進一步，對其他的影響蛋白表達的nt-RNA特有的標簽也做了生存分析。 / 最後，我檢查了nt-RNA作為診斷標記物和用來定義原发灶不明的癌症（CUP）的起源的標記物的兩大應用。只有在差異表達方面獨立於正常轉錄本的那些nt-RNA會被用作生物標記物。通過比較癌症和正常的樣本，檢查了哪些nt-RNA可以作為診斷標記物。利用無監督的聚類分析和熱圖顯示了這些nt-RNA可以很明顯地將癌症和正常樣本分開。在研究原发灶不明的癌症（CUP）的起源中，通過對訓練集（N=541）和獨立的外部驗證集（N=2462）進行交叉驗證學習，定義了一個可以識別大多數癌症樣本的nt-RNA標簽集（400個nt-RNA特有的片段標簽）。無監督的聚類分析和熱圖顯示了用這些nt-RNA定義原发灶不明的癌症（CUP）的起源的能力。隨後，通過從訓練集的樣本隨機抽樣100次，檢查了由400個nt-RNA特有的片段標簽組成的分類器的顯著性。100次隨機抽樣的結果顯示：對訓練集，樣本準確分類率的均值和標準差分別是96.4895%和0.75%；對驗證集，樣本準確分類率的均值和標準差分別是91.0239%和1.032611%。 / 總之，本研究顯示了nt-RNA有重要的生物功能和多種應用。它是癌症診斷和預後的潛在的生物標記物。它也可以被用來決定癌症的原发灶，這意味著nt-RNA將會為癌症診斷和決定原发灶不明的癌症的原发灶的這些潛在應用提供很好的信息。[附圖] / Hu, Fuyan. / Thesis Ph.D. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 173-211). / Abstracts also in Chinese. / Title from PDF title page (viewed on 12, October, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

The purpose of this study was to examine the efficacy of DIBELS Nonsense Word Fluency Scores in the fall of first grade as a predictor of SAT-10 results. A comparison of boys and girls, three ethnic groups (Caucasian, Hispanic, African-American), and three different reading risk groups were examined using multiple regression analyses. Analysis of data from a total of 27,000 participants from a cohort of Reading First schools in 2003/2004 confirmed Nonsense Word Fluency scores in the fall of first grade to be a significant predictor of the SAT-10 reading scores in the spring. Differences found between and within groups were determined very small when Cohen's effect size was calculated. These results support for the use of Nonsense Word Fluency as a valid and useful early literacy assessment tool for determining which children likely need early additional reading instructional support in order to be successful readers.

The aim of this thesis was to identify genetic factors involved in frontotemporal lobar degeneration (FTLD), a neurodegenerative disorder clinically characterised by a progressive change in personality, behaviour and language. FTLD is a genetically complex disorder and a positive family history is found in up to 40% of the cases. In 10-20% of the familial cases the disease can be explained by mutations in the gene encoding the microtubule associated protein tau (MAPT). In the first study we describe the clinical and neuropathological features of a Finnish family with FTLD caused by a mutation in MAPT. We also provide evidence that the pathogenic mechanism of this mutation is through altered splicing of MAPT transcripts. Recently, mutations in the gene encoding progranulin (PGRN) were identified as a major cause of FTLD. In the second study we describe a Swedish family with FTLD caused by a frameshift mutation in PGRN. We provide a clinical and neuropathological description of the family, as well as evidence that the pathogenicity of this mutation is through nonsense-mediated decay of the mutant mRNA transcripts and PGRN haploinsufficiency. In the third study we describe a novel PGRN splice site mutation and a previously described PGRN frameshift mutation, found in a mutation screen of 51 FTLD patients. We describe the clinical and neuropathological characteristics of the mutation carriers and demonstrate that haploinsufficiency is the pathogenic mechanism of the two mutations. In the fourth study we investigate the prevalence of PGRN and MAPT gene dosage alterations in 39 patients with FTLD. No gene dosage alterations were identified, indicating that variations in copy number of the PGRN and MAPT genes are not a common cause of disease, at least not in this FTLD patient collection.