Inherited disorders of platelet function are a rare and heterogeneous group of diseases usually characterised by a mild to moderate bleeding tendency. Typical bleeding symptoms are easy bruising, epistaxis, menorrhagia as well as mucocutaneous and perioperative bleeding. The performance of platelet function diagnostics in children is hampered by age-dependent restriction of blood sample size, poor venous access, and the lack of reproducible test reference ranges for children of different age groups. Platelet function testing is limited to specialised centres, because platelet function test procedures are complicated and time-consuming, which most likely results in a relevant number of undiagnosed and incorrectly classified children with clinically relevant platelet function defects. Evaluation of bleeding history and bleeding symptoms is essential for a rational step-bystep approach to diagnosis. Platelet function diagnostics should be preceded by the exclusion of thrombocytopenia, von Willebrand disease, and secondary haemostasis defects. Light transmission aggregometry is still considered the standard for the assessment of platelet function. Every effort should be made to classify the specific platelet function defect in the patient, because this is essential for accurate treatment and counselling. / Angeborene Thrombozytenfunktionsstörungen stellen eine seltene und heterogene Gruppe von Erkrankungen dar, welche meist durch eine leichte bis mittelschwere Blutungsneigung auffallen. Typische Blutungssymptome sind Hämatomneigung, Epistaxis, Menorrhagien sowie Schleimhaut- und perioperative Blutungen. Die Durchführung der Thrombozytenfunktionsdiagnostik bei Kindern wird erschwert durch die altersabhängig begrenzte Blutprobenmenge, schwierige Venenverhältnisse und das Fehlen von Referenzbereichen für Kinder unterschiedlichen Alters. Aufgrund der meist komplizierten und zeitaufwendigen Tests ist die Thrombozytendiagnostik auf spezialisierte Zentren begrenzt. Mit hoher Wahrscheinlichkeit wird eine relevante Anzahl von Kindern mit nichtdiagnostizierten bzw. unkorrekt klassifizierten, klinisch relevanten Thrombozytopathien übersehen. Die Erhebung der Blutungsanamnese und die Bewertung der Blutungssymptome sind erforderlich für eine stufenweise erfolgreiche Gerinnungsdiagnostik. Vor Durchführung einer Thrombozytenfunktionsdiagnostik sollten das Vorliegen einer Thrombozytopenie, einer von-Willebrand-Erkrankung und sekundärer Gerinnungsstörungen ausgeschlossen werden. Die Lichttransmissionsaggregometrie gilt noch immer als Standardmethode für die Beurteilung der Thrombozytenfunktion. Nach Möglichkeit sollte stets versucht werden, den vorliegenden spezifischen Thrombozytenfunktionsdefekt zu klassifizieren, da dies für eine adäquate Behandlung und eine gezielte genetische Beratung notwendig ist. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

This thesis describes investigations into the genetic basis and pathophysiology of three distinct inherited diseases in humans, two of which are strongly associated to the function of the ectodomain sheddase enzyme ADAM17. The first of these is a novel inherited syndrome of neonatal onset inflammatory skin and bowel disease, which is associated in a consanguineous family with homozygous loss-offunction mutations in ADAM17. This thesis describes investigations of the expression and function of ADAM17 – and downstream proteins it regulates – in an individual affected by this disease. This is accompanied by genetic investigations into other individuals suspected of suffering from the same syndrome. The second investigated disease is Tylosis with Oesophageal Cancer (TOC), an inherited cutaneous disease which represents the only known syndrome of familial oesophageal cancer susceptibility. This disease was associated to dominantly inherited mutations in the Rhomboid protein iRHOM2. This work describes investigations of immortalised keratinocyte cell lines and tissues derived from TOC-affected individuals, and illustrates that the pathogenesis of TOC is characterised by increased iRHOM2-dependent activation and activity of ADAM17, and upregulation of the shedding of ADAM17 substrates, particularly in the EGFR ligand family, accompanied by increased desmosome turnover and transglutaminase 1 activity. This pattern of upregulation results in attendant increases in growth factor signalling, proliferation and motility in TOC keratinocytes, dependent on ADAM17. The third focus of this thesis is a life-threatening inherited gastrointestinal disease (accompanied by severe extraintestinal complications) whose symptoms correspond to Cryptogenic Multifocal Ulcerative Stenosing Enteritis. This work describes the identification of mutations in cytosolic phospholipase A2-α (cPLA2α) – an enzyme responsible for arachidonic acid production, the first step in the eicosanoid synthesis pathway – as associated with this condition in a single affected family. The expression and function of cPLA2α in this disease was investigated, using platelet aggregation stimulated by a downstream product of cPLA2α (Thromboxane A2) as a model.

Background: Hypertrophic Cardiomyopathy (HCM) and Long QT Syndrome (LQTS) are genetic cardiovascular diseases that cause sudden cardiac death. When an individual is diagnosed with an inherited disease such as HCM/LQTS it is critical that their biological relatives are notified of their increased risk. Newly diagnosed individuals in turn notify other at-risk family members through a successive process called cascade screening. This facilitates screening of at-risk biological relatives through genetic testing and/or clinical testing, and treatment for HCM/LQTS prior to development of life-threatening complications. However, for cascade screening to detect all potential cases the disease risk must be effectively communicated to all at-risk relatives. The responsibility for notifying family members of this risk largely falls to the first person diagnosed in the family (proband). Empiric evidence suggests that around half of at-risk relatives are not screened in accordance with cascade screening recommendations, potentially due to information about HCM/LQTS risk not being communicated effectively in their families. Factors have been identified that influence communication about genetic risk in families with non-cardiac disease; however, it is not known if or how these factors apply in families with genetic cardiac disease. These include network factors, which describe characteristics of relationships between family members and non-network factors, which describe characteristics of individuals including individual factors, disease factors, and sociocultural factors. There is a critical need to understand communication in families with HCM/LQTS in order to facilitate effective genetic risk communication in families, improve adherence to cascade screening recommendations, and prevent death and complications from cardiovascular diseases. Objectives: The purpose of this study was to improve our understanding of the relationships among network and non-network factors and communication of genetic risk for HCM/LQTS between probands and their relatives. I proposed the following aims: Aim 1: Describe family social network structures and communication paths about risk for HCM/LQTS from probands to their relatives. Aim 2: Identify which network and non-network factors are associated with who is told about risk for HCM/LQTS. Methods: The sample for this study included individuals with HCM or LQTS recruited through the University of Iowa Cardiology Clinics (UI) and the University of Wisconsin Inherited Arrhythmia Clinic (UW). Data were collected using a structured interview, family pedigree, and survey. Analysis included egocentric social network analysis, descriptive, bivariate, and multilevel logit regression modeling. Results: Participants in this study had an average of 24 living at-risk relatives in their families. Overall, just over half (52%) of these at-risk relatives had been reported to have been told about their risk. However, within families, the percentage of relatives told about their risk ranged from 0%-100%. Ninety percent of first-degree relatives were told about their risk, 61% of second-degree relatives were told and 33% of third-degree relatives were told. Recruitment site affiliation was determined to be a confounder and so analyses were calculated separately for UI and UW. In both the UI and UW samples, network factors including closer geographic distance, increased emotional closeness, increased relationship quality, increased frequency of communication, higher betweenness centrality, and closer degree of biological relation were independently associated with increased odds of communication of risk. In the UI sample, non-network factors that were independently associated with increased odds of communication of risk included younger age at diagnosis; having LQTS; having positive genetic test results; having an ICD; younger current age; being female; having increased role limitations due to physical functioning; feeling anxious about telling family members about risk; feeling communication was a burden; feeling that communication was a responsibility or duty; being happy to be able to share important information; and identifying financial issues, pregnancies, or upcoming marriages as playing a role in communication. In a multivariate model, increased frequency of communication, closer degree of biological relation, having an ICD, and identifying financial issues and pregnancies as contributors to communication were significantly associated with communication of genetic risk information. In the UW sample, non-network factors that were independently associated with increased odds of communication of risk included younger age, decreased emotional wellbeing, increased role limitations due to emotional wellbeing, and decreased energy and fatigue. In a multivariate model, increased frequency of communication and closer degree of biological relation were significantly associated with communication. Although over half of at-risk relatives were told about their risk, just over half of those (53.8%) were reported to have screened for disease, which represents 27% of all at-risk relatives. Of those tested, 35% were reported as diagnosed with HCM/LQTS. Conclusion: Communication of genetic risk for HCM/LQTS in families is inadequate and contributes to the problem of relatives not being screened for disease. Insight on the factors that influence communication in families at risk of sudden cardiac death can guide development of interventions, policies, and future research aimed at improving genetic risk communication and cascade screening, and preventing death and complications from inherited cardiac diseases. This research is applicable for genetic conditions where population based screening methods are not effective and rely on families to communicate risk and need for screening.

Neonatal immune responses are typically deficient against a wide variety of antigens, including alloantigens, vaccine antigens, and infectious agents. These responses are characterized by Th2-skewed cytokine production, and deficient Th1 and cytotoxic responses. However, these deficient responses can be boosted to adult levels by the use of strong, Th1 promoting agents. This demonstrates that neonates are capable of developing mature immune responses under specific conditions. Using two different murine models, we have found that neonates develop robust Th and cytotoxic responses, which under some antigenic conditions significantly exceed those of adults. First, using a model of early life exposure to noninherited maternal antigens (NIMA), we found that murine neonates develop robust in vivo cytotoxic responses to low doses of alloantigens. Importantly, primary in vivo cytotoxic responses to alloantigen developed during the neonatal period, and persisted into adulthood. Neonates developed similar memory cytotoxic responses to donor spleen cells, bone marrow, and stem cell-enriched (Lin-) bone marrow cells, suggesting that the exposure dose is more important than the type of transplanted donor cell for the development of cytotoxicity. NIMA-exposed neonates also developed vigorous primary and memory allospecific Th1/Th2 responses which exceeded the responses of adults. These findings suggest that early exposure to low levels of NIMA may lead to long term immunological priming of all arms of T cell adaptive immunity. Second, we characterized the phenotype and function of neonatal recent thymic emigrants (RTE). RTE are the predominant cell type in murine neonates, and are present at higher frequencies within the neonatal CD4+ compartment than in adults. Our data demonstrate that RTE from murine neonates and adults are phenotypically and functionally distinct. In particular, although the magnitude of RTE cytokine responses from both age groups is dependent on the conditions of activation, neonatal RTE consistently exhibited higher levels of effector cytokine production than adult RTE. In particular, activation of neonatal RTE in the presence of IL-7 lead to greatly increased IFNgamma production, while adult responses were not altered. Overall, neonatal RTE responses were more plastic than those of adult RTE, as both Th1 and Th2 responses were altered in neonates using various activation conditions, while only Th2 responses were consistently changed in adults. Finally, in contrast to adult RTE, neonatal RTE proliferated in response to IL-7 stimulation at very early timepoints. This was associated with faster kinetics of IL-7Ralpha downregulation and higher levels of pSTAT5 in neonatal RTE. These quantitative and qualitative differences in neonatal RTE populations may largely explain the diverse responses that are elicited in neonates in response to different antigens, especially under those conditions in which Th1 responses are enhanced (i.e., exposure to NIMA alloantigens). Taken together, these data demonstrate that neonatal T cell responses are actually highly plastic, instead of intrinsically deficient. Furthermore, if given optimal stimulation conditions, neonatal responses can actually exceed those produced by adults.

Myoclonus-Dystonia (MD) is an inherited, rare, autosomal dominant movement disorder characterized by quick, involuntary muscle jerking or twitching (myoclonus) and involuntary muscle contractions that cause twisting and pulling movements, resulting in abnormal postures (dystonia). The first MD locus was mapped to 7q21-q31 and called DYT11; this locus corresponds to the SGCE gene. Our group previously identified a second MD locus (DYT15) which maps to a 3.18 Mb region on 18p11. Two patients were chosen to undergo next-generation sequencing, which identified 2,292 shared novel variants within the critical region. Analysis of these variants revealed a 3 bp duplication in a transcript referred to as CD108131, which is believed to be a long non-coding RNA. Characterization of this transcript determined that it is 863 bp in size, it is ubiquitously expressed, with high expression in the cerebellum, and it accounts for ~3% of MD cases.

Human Herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are ubiquitous betaherpesviruses. Both viruses are associated with a variety of adult disorders including neurological disorder, such as multiple sclerosis and chronic fatigue syndrome. HHV-6 viruses are capable of establishing latency by integration into the telomeres of the host chromosome and are transmitted in a Mendelian manner in approximately one percent of the population. To date little is known about the immunological and neurological consequences of HHV-6 inheritance. This study focused on a unique population of individuals that inherited HHV-6 and present with chronic fatigue-like symptoms, including hypersomnia, generalized fatigue, headache, and short term and long term memory impairment. The central hypothesis of this study was that active replication of HHV-6 correlates with patient symptoms. To address this aim we first looked at the reactivation of integrated HHV-6 in vitro by inducing viral replication with epigenetic modifiers trichostatin A (TSA), valproic acid, sodium butyrate, and carbamazepine, and found TSA to be an effective method of inducing reactivation of HHV-6 from its integrated form. Additionally, a reactivated HHV-6A virus isolated from a patient with inherited HHV-6 was fully sequenced and the nucleotide and amino acid sequence was compared to that of fully sequenced HHV-6 laboratory strains, as well as the inherited virus. The reactivated virus was found to be very similar to the HHV-6A GS strain; however, there was some divergence at the right end of the viral genome and regions of the genome that do not contain herpesvirus core genes. Interestingly, the sequenced reactivated virus was found to differ from the HHV-6 virus which was inherited. Finally, HHV-6 replication was assessed by performing reverse transcriptase PCR assay for the viral glycoprotein U100 in patients receiving antiviral treatment. Results indicated that short term antiviral treatment was insufficient to abrogate viral replication, while treatment of six weeks or longer eliminated viral mRNA in patient blood samples. Furthermore, sequencing of the viral mRNA and inherited viral DNA indicate that the source of the mRNA detected in patient blood samples was an exogenously acquired HHV-6 virus, as the U100 glycoprotein sequences were not identical. Together these studies indicate that although HHV-6 can be reactivated from its integrated form, individuals in this unique population harbored an exogenous HHV-6 virus, in addition to the inherited virus; we termed this condition inherited herpesvirus syndrome. The fact that these individuals are able to acquire exogenous HHV-6 viruses suggest that there may be some level of immune tolerance or immune dysfunction; we suggest that further studies focus on uncovering the immune response to HHV-6 in individuals with an inherited form of the virus.

Characterization of the RNA transcriptome by next-generation sequencing can produce an unprecedented yield of information that provides novel biologic insights. I describe four approaches for sequencing different aspects of the transcriptome and provide computational tools to analyze the resulting data. Methods that query the dynamic range of gene expression, low expressing transcripts, micro RNA levels, and start-site usage of transcripts are described.

By facilitating timely diagnosis and treatment initiation, population-wide newborn screening programs have led to important reductions in morbidity and mortality for many rare diseases, including medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Newborn screening has also expanded the spectrum of disease severity for MCAD and VLCAD deficiencies to include a higher proportion of milder cases, raising questions about appropriate disease management. To date there has been no systematic attempt to characterize best management practices in terms of the guidance that is available to those who provide care for MCAD and VCLAD deficiencies; nor has there been an attempt to understand the extent to which current practices align with such currently available guidance. The two projects that are part of this thesis sought to address these research gaps with a particular focus on two key disease-specific management practices we identified in advance as priorities: the use of carnitine supplementation and the recommended duration of fasting. The objective of the first project was to systematically review the quality and content of clinical practice guidelines and/or recommendations for the diagnosis and management of both MCAD and VLCAD deficiencies. Two independent reviewers assessed the eligibility of citations retrieved from a comprehensive search of the peer-reviewed and grey literature. We appraised the quality of the reviewed guidance and extracted information on the content of recommendations. From the 25 guidance documents that met our inclusion criteria, only 7 incorporated evidence reviews, indicating that guidance in this field does not generally meet established methodological standards for the rigorous development of clinical practice guidelines. With respect to content, we identified unclear and inconsistent recommendations regarding fasting times and the use of carnitine supplementation. Further empirical evidence in these areas is necessary to inform the development of future rigorous guidelines. The objective of the second project was to identify actual practices in the management of MCAD deficiency. We conducted a scoping review of published literature on treatment practices around the world and a secondary analysis of data documenting treatments received by participants in a Canadian pediatric cohort study. For the scoping review, citations retrieved from our comprehensive search strategy were screened by two independent reviewers. We extracted information on study characteristics and disease management. Our secondary analysis included longitudinal data for Canadian children with MCAD deficiency, born between 2006 and 2015 and enrolled in a cohort study at one of 13 centres. For both project components, we described carnitine supplementation and fasting times, overall and according to potential indicators of disease severity (genotype, biochemical phenotype). We identified 5 relevant publications in the scoping review and analyzed data for 107 children participating in the Canadian cohort. Management practices related to carnitine supplementation and fasting times for MCAD deficiency were highly variable based on both data sources. There was some evidence of an association between genotype and carnitine use, which, based on the scoping review, may be due to a relationship between genotype and carnitine deficiency. While actual practice was in some ways aligned with the guidance we reviewed in the first project, these results underscore the need for further evidence to address areas of uncertainty that have been prioritized by patients and families, clinicians, and health researchers, including questions regarding the potential to tailor treatment to predicted disease severity and an emphasis on controversial therapies such as carnitine supplementation.

Orientador: Anibal Eugenio Vercesi / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T05:29:39Z (GMT). No. of bitstreams: 1 Figueira_TiagoRezende_D.pdf: 22742066 bytes, checksum: dd66394fba07238337b8c5a2eeb0c858 (MD5) Previous issue date: 2011 / Resumo: A analbuminemia congênita é uma doença autossômica recessiva caracterizada por níveis traços de albumina plasmática (< 1 mg/mL) e sintomas clínicos leves. Entre as comorbidades apresentadas pelos indivíduos e ratos analbuminêmicos (ratos Nagase - NAR), os distúrbios no metabolismo/transporte de lipídeos plasmáticos são as mais marcantes. A dislipidemia associada à analbuminemia é caracterizada por níveis aumentados de colesterol e triglicérides, e déficit de ácidos graxos livres (FFA). Nesta tese, são apresentados três estudos independentes sobre a analbuminemia, os quais objetivaram investigar: 1) os mecanismos da hipertrigliceridemia e do déficit de FFA plasmático do NAR; 2) o metabolismo de carboidratos no NAR; 3) as funções mitocondriais no NAR. Também é apresentado um quarto estudo (aspectos metodológicos) sobre o uso do probe safranina para avaliar o potencial elétrico transmembrana mitocondrial. Os principais resultados destes estudos foram: Estudo um: as taxas de lipogênese (596 ± 40 vs. 929 ± 124 ?mol 3H2O/g/h) e de secreção de triglicérides para o plasma (4,25 ± 1,00 vs. 7,04 ± 1,68 mg/dL/min) foram mais lentas (P ? 0,05) no NAR do que no rato controle Sprague-Dawley (SDR). As injeções de heparina ou de albumina no NAR promoveram um aumento de FFA plasmático em função do tempo. Noventa minutos após a injeção de albumina, os níveis de FFA plasmáticos nos NAR se elevaram de 0,36 ± 0,05 para 1,34 ± 0,16 mEq/L (P ? 0,05), atingindo os níveis do SDR. Estes resultados indicam que a falta de albumina plasmática inibe a lipólise intravascular e causa o déficit de FFA plasmático na analbuminemia, e que a produção hepática de triglicérides não contribui para a hipertrigliceridemia no NAR. Estudo dois: a concentração de glicose plasmática foi similar entre os NAR e os SDR alimentados ou em jejum, porém a insulinemia no estado alimentado foi maior nos NAR do que nos SDR (P ? 0,05). O NAR apresentou maior tolerância à glicose quando comparado ao SDR (P ? 0,05). Esta maior tolerância a glicose está associada à maior resposta insulinêmica à administração de glicose. Não houve diferença entre os grupos para a sensibilidade periférica a insulina. Apesar do conteúdo similar de glicogênio hepático no estado alimentado, o NAR apresentou menor conteúdo de glicogênio (40% do SDR) após 6 h de jejum. A injeção de piruvato (substrato neoglicogênico) promoveu um aumento mais rápido na glicemia do NAR em comparação ao SDR. Deste modo, os resultados indicam que o NAR apresenta metabolismo de glicose acelerado. Estudo três: a capacidade de retenção de Ca2+ pelas mitocôndrias isoladas do fígado do NAR aos três meses de idade foi ~50% daquela do SDR. Esta variável não se diferiu entre os grupos quando avaliada aos 21 dias de vida dos ratos. Foi observada uma depleção de ~20% no conteúdo de nitrosotiol e um aumento de ~30% na expressão de ciclofilina D nas mitocôndrias de fígado do NAR. Nenhuma das variáveis relacionadas ao estado redox mitocondrial diferiu entre NAR e SDR, tais como: o conteúdo de tióis reduzidos, de glutationa total, a taxa de liberação de H2O2, e o estado reduzido de NAD(P)H. Com isso, conclui-se que a maior expressão de ciclofilina D, um componente importante no processo de transição de permeabilidade mitocondrial, e o menor conteúdo de nitrosotiol nas mitocôndrias dos NAR podem explicar a sua menor capacidade de retenção de Ca2+ / Abstract: Congenital analbuminemia is a rare autosomal recessive disorder characterized by a trace level of albumin in blood plasma and mild clinical symptoms. Analbuminemic patients and rats (Nagase analbuminemic rats - NAR) present associated abnormalities, among which the disturbances in plasma lipid metabolism and transport are hallmarks. The dyslipidemia associated with analbuminemia comprises a unique plasma lipid profile (i.e. high cholesterol and triglycerides, but a severe free-fatty acids deficiency). Three independent works on analbuminemia are presented in this PhD thesis, whose aims were: 1) to investigate the mechanisms of NAR hypertriglyceridemia and plasma free-fatty acids deficiency; 2) to study carbohydrate metabolism in NAR; 3) to evaluate mitochondrial (dys)function in NAR. Also, a methodological study about the use of the dye safranine as a fluorescent probe for the assessment of mitochondrial transmembrane electrical potential is presented in this thesis. The main results from these studies were: Study one: lipogenesis (596 ± 40 vs. 929 ± 124 ?mol 3H2O/g/h) and triglyceride secretion rates (4.25 ± 1.00 vs. 7.04 ± 1.68 mg/dL/min) were slower (P ? 0.05) in fasted NAR than in control Sprague-Dawley rats (SDR). The injection of either heparin or albumin elicited an increase in NAR plasma FFA levels over time. FFA levels reached control levels 90 min after the albumin administration into NAR, increasing from 0.36 ± 0.05 to 1.34 ± 0.16 mEq/L (P ? 0.05). These results indicate that the lack of plasma albumin inhibits intravascular lipolysis and causes the FFA deficit observed in NAR. Moreover, hepatic triglyceride output seems not to contribute to NAR hypertriglyceridemia. Study two: plasma glucose levels were similar between fed and fasted NAR and SDR, but fed insulinemia was higher in NAR than in SDR (P ? 0.05). NAR displayed increased glucose tolerance compared to SDR (P ? 0.05). This enhanced glucose tolerance was associated with higher insulinemia after the glucose load, and with similar insulin sensitivity between the groups. Despite similar liver glycogen content in fully fed condition, NAR had lower glycogen content (40% of control) after 6-h fasting. The injection of pyruvate (gluconeogenic substrate) elicited a faster rise in glycemia of NAR than in SDR. Therefore, NAR display enhanced glucose metabolism. Study three: the Ca2+ retention capacity of the liver mitochondria isolated from 3-month-old NAR was about 50% that of the control. Interestingly, the assessment of this variable in 21-day-old NAR and SDR indicated that the mitochondrial Ca2+ retention capacity was preserved at this age. A 20% decrease in mitochondrial nitrosothiol content and a 30% increase in cyclophilin D expression were observed in NAR liver mitochondria. None of the variables related to mitochondrial redox state differed between the controls and NAR, i.e., namely the contents of reduced mitochondrial membrane protein thiol groups and total glutathione, H2O2 release rate, and NAD(P)H reduced state. We conclude that the higher expression of cyclophilin D, a major component in the mitochondrial permeability transition process, and decreased nitrosothiol content in NAR mitochondria may underlie their lower Ca2+ retention capacity / Doutorado / Biologia Estrutural, Celular, Molecular e do Desenvolvimento / Doutor em Ciências

In recent years the study of entrepreneurial spinoffs has focused on how knowledge spillover leads to new knowledge and entrepreneurial activity. This study aims to explore the effect of a founder’s knowledge inherited from an incumbent parent company in the formation of a spinoff in the ICT sector. As a theoretical framework, the study uses An Absorptive Capacity Theory of Knowledge Spillover Entrepreneurship (Qian and Acs, 2013). Using a qualitative approach through interviews with the founder of the spinoff, this study aims to strengthen the empirical validity of these theories in a single setting. The proposed findings are strongly in line with the theory, but a certain aspect considering the help from a parent company proposes a possibility to modify the framework into a particularized framework that can be implicated to various spinoffs globally. Thus, the findings suggest that entrepreneurial activity deriving through absorptive capacity and inherited knowledge is affected by the contributions from the parent company.