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The role of pre-mRNA splicing in human hereditary diseases
Malinová, Anna
U5 small ribonucleoprotein particle (U5 snRNP) is a crucial component of the spliceosome, the complex responsible for pre-mRNA splicing. Despite the importance of U5 snRNP, not much is known about its biogenesis. When we depleted one of the core U5 components, protein PRPF8, the other U5-specific proteins do not associate with U5 snRNA and the incomplete U5 was accumulated in nuclear structures known as Cajal bodies. To further clarify the role of PRPF8 in U5 snRNP assembly, we studied PRPF8 mutations that cause an autosomal dominant retinal disorder, retinitis pigmentosa (RP). We prepared eight different PRPF8 variants carrying RP-associated mutations and expressed them stably in human cell culture. We showed that most mutations interfere with the assembly of snRNPs which consequently leads to reduced efficiency of splicing. The mutant PRPF8 together with EFTUD2 are stalled in the cytoplasm in a form of U5 snRNP assembly intermediate. Strikingly, we identified several chaperons including the HSP90/R2TP complex and ZNHIT2 as new PRPF8's interactors and potential U5 snRNP assembly factors. Our results further imply that these chaperons preferentially bind the unassembled U5 complexes and that HSP90 is required for stability of...
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The role of pre-mRNA splicing in human hereditary diseases
Malinová, Anna
U5 small ribonucleoprotein particle (U5 snRNP) is a crucial component of the spliceosome, the complex responsible for pre-mRNA splicing. Despite the importance of U5 snRNP, not much is known about its biogenesis. When we depleted one of the core U5 components, protein PRPF8, the other U5-specific proteins do not associate with U5 snRNA and the incomplete U5 was accumulated in nuclear structures known as Cajal bodies. To further clarify the role of PRPF8 in U5 snRNP assembly, we studied PRPF8 mutations that cause an autosomal dominant retinal disorder, retinitis pigmentosa (RP). We prepared eight different PRPF8 variants carrying RP-associated mutations and expressed them stably in human cell culture. We showed that most mutations interfere with the assembly of snRNPs which consequently leads to reduced efficiency of splicing. The mutant PRPF8 together with EFTUD2 are stalled in the cytoplasm in a form of U5 snRNP assembly intermediate. Strikingly, we identified several chaperons including the HSP90/R2TP complex and ZNHIT2 as new PRPF8's interactors and potential U5 snRNP assembly factors. Our results further imply that these chaperons preferentially bind the unassembled U5 complexes and that HSP90 is required for stability of...
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Possibilities of respiratory therapy in children with spinal muscular atrophy
BRŮŽKOVÁ, Romana
Spinal muscular atrophy (SMA) is a rare, progressive, genetically conditioned disease that causes muscle wasting. Depending on its type, the disease can begin to appear at an early age. As the disease progresses, muscles of the whole body begin to weaken, causing the affected person to be bound to a wheelchair, forced to use various compensation tools and is dependent on the help of others. Very common complications of this disease are e.g. scoliosis, swelling of the limbs, contractures, and respiratory problems, to which need to be responded as soon as possible, as it is very serious complication and respiratory insufficiency in advanced stages may lead to death of the affected person. It is neccessary to strengthen breathing muscles, maintain lung volume by training and keep the airways clear and clean. The main goal of this thesis was to formulate the possibilites of respiratory therapy in children with the spinal muscular atrophy and to apply selected techniques of respiratory therapy and selected aiding tools along with the evalution of the effect. The theoretical part focuses on the description of the disease, its symptoms, diagnosis, and options of treatment such as pharmacotherapy, gene therapy, medical rehabilitation and respiratory therapy, which is crucial in children with spinal muscular atrophy. The practical part is based on qualitative research, where casuistries of three children with spinal muscular atrophy are processed. The research includes kinesiological analysis, muscular test, measurement of the chest circumference and spirometric examination. Based on this examination, a therapy plan was established. Lung function in all probands at the end of the therapy was approximately the same as at its beginning, which can be considered a positive effect of selected techniques due to the fact that SMA is a progressive disease.
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The role of pre-mRNA splicing in human hereditary diseases
Malinová, Anna ; Staněk, David (advisor) ; Vanáčová, Štěpánka (referee) ; Krásný, Libor (referee)
U5 small ribonucleoprotein particle (U5 snRNP) is a crucial component of the spliceosome, the complex responsible for pre-mRNA splicing. Despite the importance of U5 snRNP, not much is known about its biogenesis. When we depleted one of the core U5 components, protein PRPF8, the other U5-specific proteins do not associate with U5 snRNA and the incomplete U5 was accumulated in nuclear structures known as Cajal bodies. To further clarify the role of PRPF8 in U5 snRNP assembly, we studied PRPF8 mutations that cause an autosomal dominant retinal disorder, retinitis pigmentosa (RP). We prepared eight different PRPF8 variants carrying RP-associated mutations and expressed them stably in human cell culture. We showed that most mutations interfere with the assembly of snRNPs which consequently leads to reduced efficiency of splicing. The mutant PRPF8 together with EFTUD2 are stalled in the cytoplasm in a form of U5 snRNP assembly intermediate. Strikingly, we identified several chaperons including the HSP90/R2TP complex and ZNHIT2 as new PRPF8's interactors and potential U5 snRNP assembly factors. Our results further imply that these chaperons preferentially bind the unassembled U5 complexes and that HSP90 is required for stability of...
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Role of family in particular life phases of the people suffering from spinal muscular atrophy
Frenclová, Tereza ; Hájková, Vanda (advisor) ; Němec, Zbyněk (referee)
The thesis deals with the role of a family in particular life phases of a person suffering from the rare disease, spinal muscular atrophy. There are three main parts. The first one defines the term family, namely its system, features and functions, and explores the particularities of a family living with a handicapped member. The second part focuses on the spinal muscular atrophy, primarily on the development objectives of individual life phases of the people suffering from the disease. Thirdly, there is a section aiming at describing the role of the people taking care of the people challenged by spinal muscular atrophy from the early childhood to the middle adulthood. Furthermore, the diploma thesis points out the effort of these people to become independent and live their lives to the fullest with the help of care assistants, partners as well as start their families. For a better comprehension of the situation, there have been made semi-structured interviews with twelve families with a member of various age suffering from spinal muscular atrophy, inquiring not only the challenged persons, but also their parents and siblings.
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Spinal muscular atrophy
Bohatá, Jana ; Šolc, Roman (advisor) ; Brynychová, Iva (referee)
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder which affects α-motor neurons in anterior horns of spinal cord resulting in progressive muscle weakness. The estimated incidence is 1:10 000 and carrier frequency 1:40-1:60. SMA is classified into four grades depending on the age of onset and its severity. Life expectancy differs according to grade of SMA, patients suffering from the most serious grades live about two years, milder could live to adulthood. This disorder is caused by mutation of the SMN1 gene which is located on the fifth chromosome. In the majority of cases the type of mutation is homozygous deletion in SMN1 gene. Keywords: Spinal muscular atrophy; neuromuscular disorder; alpha motor neurons; autosomal recessive disorder; SMN1; SMN2
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Minor forms of spinal muscular atrophy
Metelcová, Tereza ; Šolc, Roman (advisor) ; Daňková, Pavlína (referee)
Spinal muscular atrophy (SMA) is neuromuscular disorder. This disorder affects motor neurons in anterior horns of spinal cord and brainstem, and cause muscle weakness. Some forms of SMA may be cause by damage peripheral nerve. The most significant difference in the pathology of SMA emerging at the level of the spinal cord and peripheral nerves is deterioration of sensory ability. Decreased ability of sensation, due to damage to sensory nerves. Nowadays, it is known 29 forms of SMA, which differ genetically, age of onset of the disorder, severity of symptoms and life expectancy. Mutation of minor forms of SMA is very diverse. Mutated genes are located on 15 different chromosomes, including the X chromosome. Clinical symptoms of SMA is similar in most forms. Several forms has another symptom besides muscular weakness. Nowadays, it is not yet known genetic cause of all forms of SMA
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