{"id":{"repo_id":"freiburg-diss","oai_identifier":"oai:freidok.uni-freiburg.de:1425"},"canonical_url":"https://search.dev.ndltd.org/etd/freiburg-diss/oai:freidok.uni-freiburg.de:1425","repository":{"repo_id":"freiburg-diss","name":"University of Freiburg","base_url":"https://freidok.uni-freiburg.de/oai/oai2.php"},"display":{"title":"Molecular genetic investigation of the variability of the GTPase activating protein- (GAP-) related domain of the tuberous sclerosis-2 (TSC2) gene in TSC patients and healthy subjects","abstract":"Tuberous sclerosis complex is an inherited disorder characterized by the development of benign tumors in various tissues. These tumors can affect the central nervous system, skin, kidney, heart and almost any organ. The frequency is currently estimated to be 1:6000 and the variation in severity of disease is great. Epilepsy, mental retardation, renal failure and reduced life expectancy are all possible, although a number of mildly affected persons lead normal lives with no reduction in reproductive fitness. <br>Two genes and their products have been identified as causing TSC when they are defective: TSC1 on chromosome 9q34.3 codes for the protein hamartin and TSC2 on chromosome 16p13.3 codes for tuberin. Tuberin shows homology to GTPase activating proteins (GAPs) and hamartin and tuberin may interact with one another to control the cell cycle, suggesting a tumor suppressor function for these proteins. <br>Efforts to screen patient populations for mutations in both genes in this study and others have been successful in identifying a large number of mutations. However, no clustering of mutations has been shown that might allow for concentration of efforts on a particular region of either gene. Sporadic mutations in TSC1 are less frequent than in TSC2 despite the fact that half of the TSC families show linkage to TSC1 and the other half to TSC2. It has been postulated that TSC1 patients are more mildly affected and may have a higher reproductive fitness than TSC2 patients. <br>The wide distribution of mutations and the high variability in clinical manifestation of TSC further complicate the quest for genotype-phenotype correlation. If the structure and function of the protein products were clearly established, then the consequence of the great number of mutations found thus far would be known. In order to lend some context to the mutations in the patient population, a group of healthy probands was screened as a control group in exon 40 of TSC2. <br>29 sporadic mutations, 4 familial cases, 9 unclassified variations and 16 polymorphisms making a total of 58 variations from the wild-type sequence were found in the 70 patients examined for this project. 8 out of 25 healthy probands also demonstrated variations in sequence, which were classified as polymorphisms. The presence of these variations in the healthy population helps define them as non-disease causing. <br>Future screening efforts may include methods of even higher sensitivity and the control of a healthy population until the gene products are better characterized. As screening efforts improve, diagnostic methods will evolve and greatly support genetic counseling. And as more is known about the function of tuberin and hamartin the closer we will come to the possibility of a causal therapy for TSC.","abstract_html":"Tuberous sclerosis complex is an inherited disorder characterized by the development of benign tumors in various tissues. These tumors can affect the central nervous system, skin, kidney, heart and almost any organ. The frequency is currently estimated to be 1:6000 and the variation in severity of disease is great. Epilepsy, mental retardation, renal failure and reduced life expectancy are all possible, although a number of mildly affected persons lead normal lives with no reduction in reproductive fitness. &lt;br&gt;Two genes and their products have been identified as causing TSC when they are defective: TSC1 on chromosome 9q34.3 codes for the protein hamartin and TSC2 on chromosome 16p13.3 codes for tuberin. Tuberin shows homology to GTPase activating proteins (GAPs) and hamartin and tuberin may interact with one another to control the cell cycle, suggesting a tumor suppressor function for these proteins. &lt;br&gt;Efforts to screen patient populations for mutations in both genes in this study and others have been successful in identifying a large number of mutations. However, no clustering of mutations has been shown that might allow for concentration of efforts on a particular region of either gene. Sporadic mutations in TSC1 are less frequent than in TSC2 despite the fact that half of the TSC families show linkage to TSC1 and the other half to TSC2. It has been postulated that TSC1 patients are more mildly affected and may have a higher reproductive fitness than TSC2 patients. &lt;br&gt;The wide distribution of mutations and the high variability in clinical manifestation of TSC further complicate the quest for genotype-phenotype correlation. If the structure and function of the protein products were clearly established, then the consequence of the great number of mutations found thus far would be known. In order to lend some context to the mutations in the patient population, a group of healthy probands was screened as a control group in exon 40 of TSC2. &lt;br&gt;29 sporadic mutations, 4 familial cases, 9 unclassified variations and 16 polymorphisms making a total of 58 variations from the wild-type sequence were found in the 70 patients examined for this project. 8 out of 25 healthy probands also demonstrated variations in sequence, which were classified as polymorphisms. The presence of these variations in the healthy population helps define them as non-disease causing. &lt;br&gt;Future screening efforts may include methods of even higher sensitivity and the control of a healthy population until the gene products are better characterized. As screening efforts improve, diagnostic methods will evolve and greatly support genetic counseling. And as more is known about the function of tuberin and hamartin the closer we will come to the possibility of a causal therapy for TSC.","abstract_has_math":false,"creators":["Zügge, Karin Louise"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Zimmerhackl, Lothar Bernd"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":null,"date_issued":"","date_published":null,"updated_at":"2026-07-24T02:22:16Z","subjects":["GAP-verwandte Domäne","Gen","Variabilität","tuberous sclerosis","mutation analysis","genetic variability","GAP-related domain"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://freidok.uni-freiburg.de/data/1425","outbound_label":"Repository record","outbound_source":"source_url"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Zimmerhackl, Lothar Bernd"]},{"key":"dc:creator","label":"Author","values":["Zügge, Karin Louise"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:type","label":"Dc Type","values":["DoctoralThesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["GAP-verwandte Domäne","Gen","Variabilität","tuberous sclerosis","mutation analysis","genetic variability","GAP-related domain"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Tuberous sclerosis complex is an inherited disorder characterized by the development of benign tumors in various tissues. These tumors can affect the central nervous system, skin, kidney, heart and almost any organ. The frequency is currently estimated to be 1:6000 and the variation in severity of disease is great. Epilepsy, mental retardation, renal failure and reduced life expectancy are all possible, although a number of mildly affected persons lead normal lives with no reduction in reproductive fitness. <br>Two genes and their products have been identified as causing TSC when they are defective: TSC1 on chromosome 9q34.3 codes for the protein hamartin and TSC2 on chromosome 16p13.3 codes for tuberin. Tuberin shows homology to GTPase activating proteins (GAPs) and hamartin and tuberin may interact with one another to control the cell cycle, suggesting a tumor suppressor function for these proteins. <br>Efforts to screen patient populations for mutations in both genes in this study and others have been successful in identifying a large number of mutations. However, no clustering of mutations has been shown that might allow for concentration of efforts on a particular region of either gene. Sporadic mutations in TSC1 are less frequent than in TSC2 despite the fact that half of the TSC families show linkage to TSC1 and the other half to TSC2. It has been postulated that TSC1 patients are more mildly affected and may have a higher reproductive fitness than TSC2 patients. <br>The wide distribution of mutations and the high variability in clinical manifestation of TSC further complicate the quest for genotype-phenotype correlation. If the structure and function of the protein products were clearly established, then the consequence of the great number of mutations found thus far would be known. In order to lend some context to the mutations in the patient population, a group of healthy probands was screened as a control group in exon 40 of TSC2. <br>29 sporadic mutations, 4 familial cases, 9 unclassified variations and 16 polymorphisms making a total of 58 variations from the wild-type sequence were found in the 70 patients examined for this project. 8 out of 25 healthy probands also demonstrated variations in sequence, which were classified as polymorphisms. The presence of these variations in the healthy population helps define them as non-disease causing. <br>Future screening efforts may include methods of even higher sensitivity and the control of a healthy population until the gene products are better characterized. As screening efforts improve, diagnostic methods will evolve and greatly support genetic counseling. And as more is known about the function of tuberin and hamartin the closer we will come to the possibility of a causal therapy for TSC.","Tuberöse Sklerose Komplex (TSC) ist eine vererbbare Erkrankung, die durch das Auftreten von gutartigen Tumoren gekennzeichnet wird. Die Tumoren können sich im zentralen Nervensystem, der Haut, der Niere, dem Herz und fast jedem anderen Organ entwickeln. Derzeit wird eine Häufigkeit von 1:6000 angenommen, wobei die klinischen Erscheinungen bei den einzelnen Betroffenen stark variieren. Es gibt schwere Verläufe mit Epilepsie, geistiger Behinderung, Niereninsuffizienz und verminderter Lebenserwartung. Gleichzeitig sind auch Patienten bekannt, die ein normales Leben führen. <br>Zwei Gene und ihre jeweiligen Proteinprodukte sind identifiziert worden, die TSC verursachen, wenn sie Defekte aufweisen: TSC1 auf Chromosom 9q34.3 kodiert für das Protein Hamartin und TSC2 auf Chromosom 16p13.3 für Tuberin. Tuberin weist Sequenzhomologien zu bekannten GTPase-aktivierenden Proteinen (GAP) auf. Hamartin und Tuberin interagieren und üben möglicherweise Einfluß auf den Zellzyklus aus, was auf eine Tumorsuppressorfunktion dieser Proteine hinweist. <br>Durch genetisches Screening von Patientengruppen wurden eine Vielzahl von Mutationen in dieser und in anderen Arbeiten gefunden. Jedoch wurde keine Anhäufung von Mutationen in einer bestimmten Genregion festgestellt, auf die sich die Forschung konzentrieren könnte. Obwohl die Hälfte aller TSC Familien genetische Kopplung zu TSC1 und die andere zu TSC2 zeigen, sind sporadische Mutationen in TSC1 seltener als in TSC2. Es ist vermutet worden, daß TSC1 Patienten mildere Verläufe und bessere relative Fortpflanzungs-Fitness als TSC2 Patienten aufweisen. <br>Die breite Streuung der Mutationen und die hohe klinische Variabilität der Erkrankung sorgt für Herausforderungen in der Suche nach genotyp-phänotyp Korrelationen. Wäre die Struktur der Proteine aufgeklärt, würde man die Konsequenzen der Vielzahl der bisher gefundenen Mutationen eher erkennen können. Um die bekannten Sequenzvariationen in einen größeren Zusammenhang zu stellen, wurde in dieser Arbeit Exon 40 des TSC2 Gens zusätzlich in einer Gruppe gesunder Probanden untersucht. <br>In den 70 Patienten dieses Projektes sind zusammen 58 Abweichungen von der Wildtyp-Sequenz gefunden worden: 29 sporadische Mutationen, 4 familäre Fälle, 9 unklassifizierte Variationen und 16 Polymorphismen. 8 von 25 gesunde Probanden wiesen ebenfalls Sequenzveränderungen auf, die als Polymorphismen klassifiziert wurden. Diese Veränderungen in der gesunden Gruppe können somit als nicht krankheitsverursachend eingestuft werden. <br>Genetische Screeningmethoden, die noch höhere Sensitivität bieten, werden sicherlich in der Zukunft weiterentwickelt. Bis die Strukturen der TSC-Proteine bekannt werden, werden aber intensivere Untersuchungen in gesunden Populationen notwendig bleiben. Diagnostische Möglichkeiten für betroffene Familien werden ebenso mit der Zeit verfeinert und werden die genetische Beratung weiter unterstützen. Je mehr über die Funktion von Hamartin und Tuberin bekannt wird, desto näher rückt die Möglichkeit einer kausalen Therapie für TSC."]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Molecular genetic investigation of the variability of the GTPase activating protein- (GAP-) related domain of the tuberous sclerosis-2 (TSC2) gene in TSC patients and healthy subjects","Molekulargenetische Untersuchung der Variabilität der GTPase aktivierenden Protein (GAP) verwandten Domäne des Tuberöse Sklerose-2 (TSC2) Gens in TSC Patienten und gesunden Probanden"]}]}],"canonical_facts":{"dc:contributor":["Zimmerhackl, Lothar Bernd"],"dc:creator":["Zügge, Karin Louise"],"dc:description.abstract":["Tuberous sclerosis complex is an inherited disorder characterized by the development of benign tumors in various tissues. These tumors can affect the central nervous system, skin, kidney, heart and almost any organ. The frequency is currently estimated to be 1:6000 and the variation in severity of disease is great. Epilepsy, mental retardation, renal failure and reduced life expectancy are all possible, although a number of mildly affected persons lead normal lives with no reduction in reproductive fitness. <br>Two genes and their products have been identified as causing TSC when they are defective: TSC1 on chromosome 9q34.3 codes for the protein hamartin and TSC2 on chromosome 16p13.3 codes for tuberin. Tuberin shows homology to GTPase activating proteins (GAPs) and hamartin and tuberin may interact with one another to control the cell cycle, suggesting a tumor suppressor function for these proteins. <br>Efforts to screen patient populations for mutations in both genes in this study and others have been successful in identifying a large number of mutations. However, no clustering of mutations has been shown that might allow for concentration of efforts on a particular region of either gene. Sporadic mutations in TSC1 are less frequent than in TSC2 despite the fact that half of the TSC families show linkage to TSC1 and the other half to TSC2. It has been postulated that TSC1 patients are more mildly affected and may have a higher reproductive fitness than TSC2 patients. <br>The wide distribution of mutations and the high variability in clinical manifestation of TSC further complicate the quest for genotype-phenotype correlation. If the structure and function of the protein products were clearly established, then the consequence of the great number of mutations found thus far would be known. In order to lend some context to the mutations in the patient population, a group of healthy probands was screened as a control group in exon 40 of TSC2. <br>29 sporadic mutations, 4 familial cases, 9 unclassified variations and 16 polymorphisms making a total of 58 variations from the wild-type sequence were found in the 70 patients examined for this project. 8 out of 25 healthy probands also demonstrated variations in sequence, which were classified as polymorphisms. The presence of these variations in the healthy population helps define them as non-disease causing. <br>Future screening efforts may include methods of even higher sensitivity and the control of a healthy population until the gene products are better characterized. As screening efforts improve, diagnostic methods will evolve and greatly support genetic counseling. And as more is known about the function of tuberin and hamartin the closer we will come to the possibility of a causal therapy for TSC.","Tuberöse Sklerose Komplex (TSC) ist eine vererbbare Erkrankung, die durch das Auftreten von gutartigen Tumoren gekennzeichnet wird. Die Tumoren können sich im zentralen Nervensystem, der Haut, der Niere, dem Herz und fast jedem anderen Organ entwickeln. Derzeit wird eine Häufigkeit von 1:6000 angenommen, wobei die klinischen Erscheinungen bei den einzelnen Betroffenen stark variieren. Es gibt schwere Verläufe mit Epilepsie, geistiger Behinderung, Niereninsuffizienz und verminderter Lebenserwartung. Gleichzeitig sind auch Patienten bekannt, die ein normales Leben führen. <br>Zwei Gene und ihre jeweiligen Proteinprodukte sind identifiziert worden, die TSC verursachen, wenn sie Defekte aufweisen: TSC1 auf Chromosom 9q34.3 kodiert für das Protein Hamartin und TSC2 auf Chromosom 16p13.3 für Tuberin. Tuberin weist Sequenzhomologien zu bekannten GTPase-aktivierenden Proteinen (GAP) auf. Hamartin und Tuberin interagieren und üben möglicherweise Einfluß auf den Zellzyklus aus, was auf eine Tumorsuppressorfunktion dieser Proteine hinweist. <br>Durch genetisches Screening von Patientengruppen wurden eine Vielzahl von Mutationen in dieser und in anderen Arbeiten gefunden. Jedoch wurde keine Anhäufung von Mutationen in einer bestimmten Genregion festgestellt, auf die sich die Forschung konzentrieren könnte. Obwohl die Hälfte aller TSC Familien genetische Kopplung zu TSC1 und die andere zu TSC2 zeigen, sind sporadische Mutationen in TSC1 seltener als in TSC2. Es ist vermutet worden, daß TSC1 Patienten mildere Verläufe und bessere relative Fortpflanzungs-Fitness als TSC2 Patienten aufweisen. <br>Die breite Streuung der Mutationen und die hohe klinische Variabilität der Erkrankung sorgt für Herausforderungen in der Suche nach genotyp-phänotyp Korrelationen. Wäre die Struktur der Proteine aufgeklärt, würde man die Konsequenzen der Vielzahl der bisher gefundenen Mutationen eher erkennen können. Um die bekannten Sequenzvariationen in einen größeren Zusammenhang zu stellen, wurde in dieser Arbeit Exon 40 des TSC2 Gens zusätzlich in einer Gruppe gesunder Probanden untersucht. <br>In den 70 Patienten dieses Projektes sind zusammen 58 Abweichungen von der Wildtyp-Sequenz gefunden worden: 29 sporadische Mutationen, 4 familäre Fälle, 9 unklassifizierte Variationen und 16 Polymorphismen. 8 von 25 gesunde Probanden wiesen ebenfalls Sequenzveränderungen auf, die als Polymorphismen klassifiziert wurden. Diese Veränderungen in der gesunden Gruppe können somit als nicht krankheitsverursachend eingestuft werden. <br>Genetische Screeningmethoden, die noch höhere Sensitivität bieten, werden sicherlich in der Zukunft weiterentwickelt. Bis die Strukturen der TSC-Proteine bekannt werden, werden aber intensivere Untersuchungen in gesunden Populationen notwendig bleiben. Diagnostische Möglichkeiten für betroffene Familien werden ebenso mit der Zeit verfeinert und werden die genetische Beratung weiter unterstützen. Je mehr über die Funktion von Hamartin und Tuberin bekannt wird, desto näher rückt die Möglichkeit einer kausalen Therapie für TSC."],"dc:format.medium":["application/pdf"],"dc:subject":["GAP-verwandte Domäne","Gen","Variabilität","tuberous sclerosis","mutation analysis","genetic variability","GAP-related domain"],"dc:title":["Molecular genetic investigation of the variability of the GTPase activating protein- (GAP-) related domain of the tuberous sclerosis-2 (TSC2) gene in TSC patients and healthy subjects","Molekulargenetische Untersuchung der Variabilität der GTPase aktivierenden Protein (GAP) verwandten Domäne des Tuberöse Sklerose-2 (TSC2) Gens in TSC Patienten und gesunden Probanden"],"dc:type":["DoctoralThesis"]},"updated_at":"2026-07-24T02:22:16Z"}