Publications from Karolinska Institutet

    Structural enzymology of the biosynthesis of polyketide antibiotics

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    Anthracyclines are an important group of aromatic antibiotics that exhibit antitumour activity, which makes them useful in treatment of various cancers. They are synthesised in the polyketide biosynthetic pathway as secondary metabolites by different Streptomyces species. An increasing number of anthracyclines have however been shown to exhibit cardiotoxic side-effects. The genetics and enzymology of this pathway has recently attracted considerable interest, not at least with the possible prospect for the production of novel antibiotics. In this thesis some of the enzymes involved in biosynthesis of anthracyclines have been studied by protein crystallography and biochemical methods. The structure of SnoaL, a stereospecific cyclase was determined to a resolution of 1.35 A as a complex with a product analogue. SnoaL belongs to a hitherto uncharacterised family of enzymes with alpha+beta barrel like fold and catalyses a novel form of intramolecular aldolcondensation. The structure of the methylesterase RdmC in complex with product analogue shows the common alpha/beta hydrolase fold and contains a catalytic SerHis-Asp triad. RdmB is a hydroxylase built up by a Rossman-like fold common to methyltransferases. The enzyme utilizes the SAM moiety in a novel way as a cofactor in the hydroxylation reaction. DnrK is a methyltransferase with a structure very similar to that of RdmB. RdmB and DnrK are thus two enzymes sharing the same fold but catalysing different reactions. They are illustrative examples of two enzymes evolved through divergent evolution. A common feature to all the enzymes studied in the thesis is that they bind their anthracycline substrates mainly through hydrophobic interactions with the involvement of only a few hydrogen bonds. Many of the enzymes have a very broad substrate specificity which might be due to these features

    Att som förälder få en cancersjukdom : Erfarenheter av föräldraansvar

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    Parents with cancer - the experiences of family responsibility Then main aim of this study was to gain an understanding of how women and men with cancer illnesses, looking after children at home, experience and manage their life situation, with focus on the responsibility as parent. An additional aim was to identify the parents' need for support, in order to develop support activities for them from a family nursing perspective. The perspective of symbolic interactionism influenced the qualitative studies in the thesis. Concepts used in the thesis were transition, identified as a core concept in nursing, and mothering and ethics of care as sensitizing concepts. The emphasis was on a conceptual framework in nursing, encompassing the main components of the theory of transition. The analysis methods used were grounded theory (study I and III), interpretive description (study II) and secondary analysis (study IV). Data was collected from open interviews with women and men with cancer who had children living at home. The participants in study I were nine women with breast cancer, in study II, eight men with cancer in the circulatory system and in study III, ten women with cancer in blood systems and a focus group interview. Study IV involved the same participants as study I and III. The results of study I illustrate the main theme of how the lives of these women had changed: transforming the exhausting-toenergising process of being a good parent in the face of cancer. All of the women expressed the desire to be a good mother. In study II, a central theme was generated - change in self-image as a man and as a parent. The men's self-image changed as well as their function as parents. In study III the core concept identified was the experience of dealing with the moral responsibility of being a mother with cancer. The findings were presented as a life story where the women's experiences were weaved together. In Study IV, the three phases in the transition process were used and a main theme was constructed that integrated these phases: "the desire to manage one's responsibility as a parent" within the context of mothering. All of the women included in this study expressed the need for professional support to help them to endure treatment procedures as well as to sustain their moral responsibility as good mothers. A model for professional moral support is suggested, based on these findings. The research implications are that the concept of moral support has been identified and can be incorporated into a theoretical model in order to further generate a hypothesis with the aim of creating a useful clinical intervention model. The clinical implications of this are to use and evaluate the tentative model for moral support in clinical practice in patient encounters with the family and in training health care staff

    Acute pesticide poisonings in Nicaragua : Underreporting, incidence and determinants

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    Background: Acute pesticide poisonings (APP) are a public health problem in Nicaragua. The quality and coverage of APP´s register, the real incidence of APP, the main determinants, the economic cost of treating cases and the effectiveness of educational intervention are not well known. Aim: The overall aim was to investigate the acute health impact of pesticide use and to discuss the possible effectiveness of preventive measures in Nicaragua. The specific aims were to calculate the proportion of APP cases officially registered, to estimate one year cumulative incidence of APP cases among population 15 years and older, to identify the main determinants related to APP among pesticide sprayers and to evaluate the impact of an integrated pest management (IPM) training intervention. Methods: For studies 1, 2, and 3, data concerning pesticide exposure and health effects were assessed in a nationally representative survey of 3169 persons 15 years and older in year 2000. For study 1, to estimate the proportion of underreporting of APP cases, the cases reported at the official surveillance system were cross matched with the casesreported through the survey. In study 2, based on self reported cases we estimated the one year incidence rate and the number of expected cases of APP in the country. In study 3, after regression analysis, the main determinants for APP among agricultural sprayers were identified. Study 4 assessed the impact of a 2 years IPM training to reduce economic costs and acute adverse health effects among 1200 basic grain farmers comparing the group of trained farmers and a group of "control" farmers who did not receive training. Results: Less than 5% of medically treated APP cases were reported to the official register. The one year APP incidence among general population was 2.3% (95%CI 1.7-2.8). The rate was higher among men, rural population and agricultural workers. More than 66,000 cases were estimated to occur yearly. The national incidence rate of APP among sprayers was extremely high, 8.3% (95% CI 5.8-10.8) and more than 34,000 cases were estimated to occur among pesticide sprayers, and representing 52% of all APP s estimated in year 2000. Although most of the cases were minor and moderate, the poisonings caused near 340,000 disability days. The causal agents for APP in 95% of cases were WHO Class I-II pesticides. The main determinants of APP among sprayers were: backpack pump leakage and incomplete or no use of personal protective equipment. Seventy seven percent of cases were caused by pesticides proposed to be banned or restricted in Central America. The IPM training prevented acute health effects and maintained productivity: after two years of training, the trained farmers used fewer pesticides, spent less money on pest control, made higher net returns, and suffered less exposure to cholinesterase-inhibiting pesticides compared to farmers who did not receive IPM training. Conclusion: Underreport figures leads to an erroneous interpretation of acute pesticide health effects. There is a high APP incidence rate in the general population, but it is four times higher among sprayers, causing important loss of or productivity and important economic costs. IPM interventions were successful in prevent the occurrence of APP cases and economic losses. Traditional prevention and control measures are insufficient and structural changes, including pesticides banning and restriction, and change to IPM agriculture models, are needed to transform the underlying determinants

    Nitric oxide and eicosanoids : Significance and interactions during antigen-induced responses in peripheral lung tissue

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    Asthma means difficulty in breathing and is described as a chronic, inflammatory disorder that produces narrowing of the lower respiratory tract. The allergen-induced asthmatic bronchoconstriction is primarily caused by an IgE-mediated release of the mast cell mediators, histamine and eicosanoids (leukotrienes and prostanoids). Asthmatics have elevated levels of nitric oxide (NO) in the exhaled air, which been proposed as a sign of airway inflammation. In the airways, mast cells represent a major source of NO. This formed NO may act in an autocrine fashion to suppress mast cell function, including release of histamine and leukotriene synthesis, and thereby be a regulator of allergen-induced responses. Nevertheless, the function of NO in the peripheral lung is not clear. The aim of this thesis was therefore to establish the role of nitric oxide and eicosanoids during early allergic airway responses in the peripheral lung. Antigen-induced contractions to the allergen ovalbumin were studied in the lung parenchyma obtained from actively sensitized guinea pigs, an in vitro-model for mast cell driven antigen-induced contractions. The peripheral lung is a complex tissue with airway smooth muscle, bronchioles, vessels and connective tissue. To further understand and characterize the contractile responses obtained to allergen or agonists in lung parenchymal tissue, studies in guinea pig precision cut lung slices (GP PCLS) were established and performed. Another aim of this thesis was also to compare species differences during the early allergic airway response in the PCLS. Inhibition of nitric oxide synthase (NOS) enhanced the contractions to cumulative doses of ovalbumin, whereas addition of the different NO donors SNP and NCX 2057 attenuated the antigen-induced contractions. The action of NO was however not relaxation of airway smooth muscle, since NO potently dilated precontracted vascular preparations and weakly relaxed precontracted tracheal rings, while there was no effect on precontracted GPLP. Instead, NO act as inhibitor of allergen-induced mediator release in the peripheral lung. Inhibition of endogenous NO increased the release of leukotrienes, whereas SNP and NCX 2057 distinctly inhibited the release of histamine or leukotrienes during antigen challenge. In conclusion, the findings support that endogenous NO has a protective role in the peripheral lung as a beneficial immunomodulator of the early allergic airway response. The findings also indicate that different NO donors may have selective and protective anti-inflammatory effects in the peripheral lung tissue. The GP PCLS was established and represents now a new in vitro model to simultaneously measure airway and vascular responses under cell culture conditions. The study showed that the pharmacology of the guinea pig PCLS most closely resembled that of the corresponding human tissues. In guinea pigs and humans, leukotrienes and prostanoids were primary mediators of the antigen-induced bronchoconstriction. In contrast, the contractile response to antigen in rat PCLS was mainly mediated by serotonin and modulated by locally formed prostanoids, in particular COX-2 derived PGE2, acting at EP1 receptors. Thus, mechanisms by which eicosanoids contribute to the early allergic airway response differ among species

    Study of pruritus in psoriasis vulgaris : Role of tachykinins

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    Pruritus has not been considered as the most important symptom of psoriasis. In the present thesis various methodologies have been used to investigate this symptom in psoriasis. The focus groups created a proper atmosphere for discussion on different aspects of pruritus in psoriasis. Pruritus was most common on the lower back and legs. Stress, cold weather and skin dryness were considered as the most common worsening factors for the condition. Sunbath and application of emollients with or without corticosteroids and calcipotriol cream were suggested as factors that relieved pruritus. Quality of life was affected in some patients. A comprehensive questionnaire was used to investigate in detail about pruritus in psoriasis. The frequency and intensity of pruritus were higher in women. Lower leg and scalp were reported as being the most commonly affected sites. Major aggravating factors were stress and dryness of skin. Sun, sleep and vacation could relieve to the condition. The most common anti-pruritic treatments used by the patients were topical glucocorticoids, vitamin D and emollients, while antihistamines were used by a small number of patients. Mood, concentration and sleep were negatively affected by pruritus. Substance P, neurokinins A (NKA), B (NKB) and NK-2 receptor (R), reactive nerves and substance P, NKA, NKB and their respective receptors NK-1, NK-2 NK-3 reactive inflammatory cells were more numerous in lesional than non-lesional psoriasis and healthy control skin, respectively. The pruritus intensity and number of NK-2R positive cells in lesional psoriatic skin were significantly correlated. Intradermally injected substance P induced pruritus, flare and wheal in psoriasis patients. Substance P (10-5 mol/L) induced a tendency to larger intensity of pruritus in lesional than non-lesional psoriatic skin. Histamine produced a shorter itch latency period in lesional and smaller wheal in non-lesional psoriasis skin compared to healthy individuals. In conclusion, pruritus is one of the common symptoms of psoriasis. Members of the tachykinin family might play an important role in the pathogenesis of pruritus in this disease

    Epidemiological and recovery facilitating studies of an urban population of stroke patients in Iran

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    Introduction Approximately 15 million people have a stroke annually in the world, of whom one third will die within one year and one third will suffer permanent disability. Over 85% of these deaths happen in people living in low- and middle-income countries. Existing evidence indicates motor impairment as the most common disability caused by stroke. Following stroke, mood disorder and cognitive impairment may either directly or indirectly lead to more significant impairments in daily activities, which require more careful services and sometimes institutionalization of the stroke patients. AMPH-like drugs are reported to enhance motor recovery, Activities of Daily Living (ADL), mood, and cognition in stroke rehabilitation, but results from trials with humans are inconclusive. Aims The main objectives of this PhD thesis were to estimate epidemiological aspects of stroke among an urban population in Iran and also to investigate the potential for ―rehabilitation pharmacology‖ of stroke recovery. Our interventional studies are aimed to investigate if levodopa (LD) and /or methylphenidate (MPH) in combination with physiotherapy can improve functional motor recovery, ADL, mood, and cognition in stroke patients. Material and methods The epidemiological studies were multihospital-based, cross-sectional and were performed on patients with stroke admitted to the hospitals in Qom-Iran from January 1st, 2001 through January 1st, 2002 (Study I) and between March 2006 and September 2007 (Study II). In the interventional studies (Study III & IV), a randomized, double-blind, placebocontrolled trial with ischemic stroke patients randomly allocated to one of four treatment groups of either MPH, LD or MPH + LD or placebo combined with physiotherapy was performed. Stroke patients were enrolled within 15 to 180 days after stroke onset. Motor function, ADL, stroke severity, mood, and cognition were assessed by Fugl-Meyer (FM), Barthel Index (BI), National Institute of Health Stroke Scale (NIHSS), Geriatric Depression Scale (GDS), and Mini Mental State Examination (MMSE) at baseline, 15, 90, and 180 days, after start respectively. Results Epidemiological studies: stroke crude rate in Qom city was estimated to be 53/100.000 per year in 2001 and the age-standardized incidence (to the European population) was 384 per 100,000 person-years. In study II the mean age of patients was 68 years. Hypertension was found in 64% of patients, followed by diabetes mellitus in 36%, heart disease in 34%, hypercholesterolemia in 32%, and smoking in 20%. Interventional studies: Motor function and ADL were recovered for all participants during treatment and at 6-month follow-up. There were slight but significant differences in BI and NIHSS compared to placebo at the 6 month follow-up. Mood and cognitive status demonstrated continuously significant improvement in all four groups across baseline and the three follow-ups but the strongest improvement was found between baseline and first follow-up immediately after the intervention. A significant improvement in mood compared to placebo was found with the combined treatment (MPH+LD) at 90 and 180 days. Conclusion Stroke incidence was higher than in Western countries. Hypertension and Diabetes mellitus were more frequent than average global findings. One month case fatality was higher than in European countries but less than in developing countries. We strongly recommend establishing a stroke registry, improved primary and secondary prevention as well as promoting rehabilitation facilities in Iran. A daily dose of LD 100 mg and /or MPH 20 mg combined with physiotherapy for 15 drug therapy sessions were safe and well tolerated and significantly improved mood status in ischemic stroke patients. It showed a slight ADL and stroke severity improvement over time and future studies should determine the optimal therapeutic window for and dosage of psychostimulants, as well as to identify those stroke patients who may benefit from treatment

    Candidate genes and the dopamine system : Possible implications in complex neurological and psychiatric disease

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    The mesencephalic dopamine (DA) system is strongly involved in the pathogenesis of Parkinsons disease (PD), where symptoms occur after the loss of the vast majority of DA neurons. An involvement of this system also in schizophrenia (SZ) and bipolar disease (BD) is suggested by the fact that DA receptor antagonists are among the most potent drugs in clinical use for the treatment of these conditions. Basic science of the past years has provided several clues for how DA cells develop and under which conditions they thrive. Different approaches include research on neurotrophic factors (providing target-derived support for DA cells), neuropeptides (modulators of neurotransmission), transcription factors (activating a large number of "downstream" genes important for development and maintenance of the cell) and endogenous as well as environmental neurotoxins. This thesis describes an effort to link basic science knowledge of the type described above to clinical samples employing the candidate gene approach. Analyzing genes encoding the above-mentioned proteins in material from patients suffering from PD, SZ and BD aims at establishing direct links between mutations in such genes and susceptibility for die disorders. The CALCA locus is one of the first and by now most well-characterized examples of alternative splicing of genes in humans. While the calcitonin protein is localized to C-cells of the thyroid gland, the alternatively spliced protein CGRP is a neuropeptide with multiple functions within the brain. We identified several new polymorphisms in this locus and investigated association within available materials from PD, SZ and BD patients. No significant associations were found with these disorders. However, the report of the sequence variations identified in the gene may still be valuable markers, since CGRP has been strongly implicated both in hypertension and migraine. NURR1 is a nuclear receptor being absolutely essential for the development of mesencephalic dopamine neurons. Three different unique missense mutations were identified in patients suffering from psychosis (two in SZ, one in BD). All three mutations were located within 78 bp from each other in a region of exon 3 and disturbed NURR1-mediated transcription similarly when modeled in vitro. Since the NURR1 gene is highly conserved between humans and rodents, introduction of the identified mutations in transgenic animals may lead to a valid model for psychosis susceptibility The ADH4 gene codes for in alcohol dehydrogenase (ADH) that converts retinol to retinal and also acts upon a wealth of other alcohols and aldehydes, some of which have been implicated in the pathogenesis of PD as endogenous or exogenous neurotoxins. We found significant association between one of several polymorphisms identified in this gene and idiopathic PD. In a follow-up study of a larger material several genes within the ADH cluster including ADH4 were analyzed. The previously found association of ADH4 with PD remained significant, while other polymorphisms did not show significant association. A nonsense mutation in ADH1C was identified in three (of 123) PD patients but none of 127 control individuals. An effort was also made to characterize the usefulness of available postmortem material for immunohistochemistry Using a plethora of different antibodies, we could confirm the feasability of postmortem studies on the protein level and found a new marker for corpora amylacea, namely nestin. Since bodies made of aggregated proteins play roles in a number of neurodegenerative disorders, we went on to characterize corpora amylacea further with antibodies against alpha- synuclein, PGP9.5 and other (vimentin, NF) neurofilaments, Expression of different alcohol and aldehyde dehydrogenases was also studied in postmortem human brain tissue using in situ hybridization. High and specific expression of an aldehyde dehydrogenase (ALDH1) was found in human DA cells. Furthermore, ALDH1 mRNA levels were found to be strongly decreased in remaining dopamine neurons of substantia nigra of PD patients as compared to controls. Other DA neurons (of the ventral tegmental area) showed normal levels of expression, indicating a selective decrease of ALDH1 mRNA levels in neurons degenerating in PD. To summarize, evidence for the involvement of alcohol- and aldehyde dehydrogenases as wed as the nuclear transcription factor NURR1 in the pathogenesis of the diseases of interest was found in the available material. Further studies along these lines using larger materials employing more markers and probes are warranted

    Mitochondrial dysfunction in ageing and degenerative disease

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    The cytoplasm of eukaryotic cells contains a dynamic network of double-membraned organelles, called mitochondria, which perform the process of oxidative phosphorylation (OXPHOS) that provides cellular energy in the form of ATP. The respiratory chain creates an electrochemical gradient across the inner mitochondrial membrane, which drives ATP synthesis by the ATP synthase. Mitochondria are indispensable for normal cell function and survival, and dysfunction of the OXPHOS system can lead to a variety of disease syndromes, collectively termed mitochondrial encephalomyopathies. Mitochondrial dysfunction has also been proposed to be involved in age-associated diseases such as diabetes mellitus, heart disease and neurodegeneration, as well as in the ageing process itself. Tissues with high metabolism seem to be particularly vulnerable to mitochondrial dysfunction and myopathy is one of the common phenotypes in mitochondrial disorders. However, the pathophysiological mechanisms linking respiratory chain deficiency to the various phenotypic manifestations are poorly understood. We therefore generated a mouse model for mitochondrial myopathy by tissue-specific disruption of the nuclear gene encoding mitochondrial transcription factor A (TFAM). These myopathy mice develop a progressive respiratory chain dysfunction in skeletal muscle with typical morphological changes consistent with mitochondrial myopathy. Surprisingly the overall mitochondrial ATP production rate was close to normal in the knockout muscles, likely due to the compensatory increase of mitochondrial mass in the affected muscles. Thus, other factors besides ATP deficiency are likely of importance in mitochondrial myopathy. There is a large number of correlative studies suggesting that mitochondrial dysfunction in skeletal muscle is causing the peripheral insulin resistance observed in patients with diabetes mellitus type 2 (DM2). Unexpectedly, the myopathy mice exhibited normal insulin sensitivity and increased glucose uptake in skeletal muscle, suggesting that reduced respiratory chain function in peripheral tissues may be protective against DM2. The mitochondrial theory of aging proposes that oxidative damage to mitochondrial DNA (mtDNA) leads to mutations and impaired respiratory chain function, which in turn, increases reactive oxygen species (ROS) production. ROS have been suggested to induce oxidative damage to various molecules of the cell and thereby cause the progressive decline seen in ageing. We generated mice expressing a proof-reading-deficient version of the mtDNA polymerase gamma. These mtDNA mutator mice accumulated mtDNA mutations at an increased rate and developed a progressive respiratory chain deficiency. They also developed premature ageing phenotypes and exhibited a reduced lifespan, supporting the suggestion of a causative link between mitochondrial dysfunction and ageing. However, we found no differences in ROS production, no increased expression of ROS scavenging enzymes, and no or minor changes in levels of oxidative damage in cell lines and tissues from the mtDNA mutator mice. We instead propose that the accumulation of mtDNA mutations beyond a critical threshold leads to bioenergetic failure and loss of vital cells. This cell loss caused by respiratory chain dysfunction may lead to reduced organ function and eventually organ failure, giving rise to age-associated disease and important ageing phenotypes

    Teleost retina : A model to study neurogenesis and angiogenesis

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    Teleost models, zebrafish and medaka have become popular models to study various aspects of developmental biology and genetics. The rapid embryonic development, transparent embryos and the availability of many mutants for various developmental and molecular pathways contribute to the usefulness of these models. The availability of various biochemical, molecular and genetic techniques applicable on these models facilitate in dissecting developmental processes. Teleost retina shows very high similarity to that seen in mammalian retina. The arrangement of the six types of neurons and one type of glia is very similar. Zebrafish has been extensively used in gaining insight into the development and functioning of the retina. Medaka, on the other hand has not been so extensively capitalized as zebrafish. The current study characterizes expression of genes mainly from the nuclear receptor family and establishes the role of zebrafish liver x receptor in governing the size, patterning and neurogenesis of the retina in zebrafish. We also establish the time line of the retinal patterning of medaka retina. Zebrafish and medaka retina show both similarity and difference in the developmental events governing the patterning of the retina. In zebrafish, retinal neurogenesis follows a fan gradient pattern starting at the ventro-nasal region. In medaka, neurogenesis starts from the central retina. An additional, second domain of neurogenesis is seen with the patterning of photoreceptors in medaka. This observation highlights the possibility of utilizing these two species as comparative models in gaining rapid understanding of retinal development and function. This study also establishes the time line of vascular development in the zebrafish retina, an important event required for normal function. Similar to neurogenesis, vasculaturedevelops rapidly and this feature was utilized to develop a small molecule-screening assay. The screening resulted in identification of five compounds that produced phenotype ranging from decrease in the number of vessels to loss of vessels specifically in the retina. To gain insight into the mode of action, further analyses of three of the five identified compounds, using either morpholino knockdown or structural similarity search was done. This study highlights the advantage of using zebrafish model to perform medically relevant chemical screen

    Genomic and epigenetic investigations of Silver-Russell syndrome and growth restriction

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    A combination of genes, their epigenetic regulation, and the environment control the phenotypes of an individual, such as how short or tall one grows. Epigenetics refers to chemical modifications of DNA and histones that regulate gene activity and genome stability, and can take the form of, for example, addition of a methyl group to DNA. A rare but illustrative example of growth restriction is Silver-Russel syndrome (SRS), which also features a relatively large, triangular head and asymmetry between body halves. Molecular studies have demonstrated that SRS is an interesting model for how growth is controlled by both genetic architecture and epigenetics, and recurring findings include DNA hypomethylation at an imprinted region on chromosome 11 (H19 ICR) in 20-65% of cases, maternal uniparental disomy of chromosome 7 (matUPD7) in 5-15%, and rare maternal duplications of chromosomes 7p and 11p. Imprinting is a rare but remarkable epigenetic phenomenon that describes parent-of-origin dependent gene activity, such that some genes are only expressed if they were inherited from, for example, the father. Differential DNA methylation (for example, maternal but not paternal methylation) is thought to regulate imprinting. All of the above mentioned molecular findings in SRS can cause dysregulation of imprinted genes. Interestingly, a large proportion of SRS patients remains molecularly unexplained. In this thesis we applied genome-wide genotyping and targeted epigenetic studies of imprinted genes to investigate the genetic nature of SRS and to disentangle the epi(genotype) and phenotype correlations in SRS and growth restriction. We devised a new approach to confirm UPD by the use of genotyping arrays and demonstrated a much increased resolution compared to the commonly used microsatellite markers. We further demonstrated the power of using genome-wide genotyping arrays in rare disorders such as SRS where UPD, copy number variants, or shared homozygosity might occur. We identified pathogenic submicroscopic events on chromosomes 15, 22, and X in molecularly unexplained SRS patients. A simple method for quantification of locus-specific DNA methylation is described and its accuracy and quantitative nature are demonstrated. In addition, reference distributions of DNA methylation at imprinted genes in controls are defined. This method was used to evaluate H19 ICR DNA methylation in SRS and isolated growth restriction, and 62% of SRS patients were hypomethylated. We further found a dose-response relationship between the degree of H19 ICR hypomethylation and phenotype severity in SRS and reported for the first time the association of specific anomalies of the spine, elbows, hands and feet, and genital defects in SRS with severe hypomethylation. In conclusion, we showed the utility of genotyping arrays to identify both UPD and submicroscopic genomic aberrations, and demonstrated that this genome-wide approach also enables the identification of important but unexpected events. Importantly, screens using genotyping arrays have the potential to detect the majority of genomic events in SRS. Through targeted epigenetic analysis we could conclude that H19 ICR methylation is clinically important as demonstrated by a strong correlation between the degree of hypomethylation and SRS phenotype severity and specifically associated clinical findings
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