Spinal Müsküler Atrofi Hastalığında Görülen Fenotipik Çeşitliliğin İnsülin Benzeri Büyüme Faktörleri ve Bağlayıcı Protein Düzeyleri ile İlişkisi
Özet
Yeşbek Kaymaz, A. Spinal Muscular Atrophy Phenotype Variations and Insulin Like Growth Factors/Binding Proteins. Hacettepe University Institute of Health Sciences Medical Biology Programme, Doctor of Philosophy Thesis, Ankara, 2017. Spinal muscular atrophy is a neuromuscular disease, which characterized by motor neuron degeneration and skeletal muscle atrophy, causing infant or early childhood death. Although it has been known that mutations in survival of motor neuron 1 (SMN1) gene cause the disease, the factors that have role in disease pathogenesis and phenotype variation are still not understood evidently. Insulin like growth factors (IGFs) are pleiotropic factors that have critical role in survival, homeostasis and maintenance of skeletal muscle and motor neuron cells. Considering their functions, it was hypothesized that IGFs might be involved in phenotype variation in SMA; therefore, liver-derived IGF system elements in circulation and their local synthesis in skeletal muscle biopsies of SMA patients were investigated in this study. The levels of main IGF system elements in serum, including IGF1, IGF binding protein (IGFBP) 3, IGFBP5 and acid labile subunit (ALS) proteins, were investigated by immunoradiometric and enzyme linked immunosorbent assay in 15 SMA patients and 18 healthy controls. The statistical evaluation of the results showed that decrease of IGF1 and increases of IGFBP5 levels in patients were significant. It was remarkable that 27 % of SMA patients had IGF1 standard deviation score under -2, as an indicator of IGF1 therapy. Decrease of IGFBP3 and ALS levels in SMA patients were not found statistically significant. The analysis of the effects of IGF system elements on phenotype variation in SMA showed that type I patients had lower serum IGF1, IGFBP3 and ALS levels when compared to type II patients, who had milder phenotype. Although the difference was not statistically significant, it might considered to have biological implications. The expression of main IGF system elements including IGF1, IGF2, IGFBP5 and IGF1 receptor in archieved skeletal muscle biopsies of 9 SMA patients, 4 healthy controls and 6 patients having non-SMA neuromuscular diseases were also investigated by immunofluorescent staining. More intense immunostaining was detected in atrophic fibers comparing to hypertrophic ones in the skeletal muscle of SMA patients with a variation among patients and the different sections of the same biopsy sample. Obtaining the same results in other neuromuscular diseases indicated that increases in IGF system elements were independent of disease pathogenesis or the atrophic fiber type and IGF system dysregulation was not disease spesific and considered as a condition occuring in skeletal muscle atrophy.
