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This dissertation, Developmental and physiological consequences of sodium/myo-inositol co-transporter 1 deficiency by Fung-ling, Jenny, Chau, 周鳳玲, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Developmental and physiological consequences of sodium/myo-inositol co- transporter 1 deficiency Submitted by CHAU, Fung Ling Jenny for the degree of Doctor of Philosophy at the University of Hong Kong in September 2005 Sodium/myo-inositol co-transporter-1 (SMIT-1) is one of the transporters responsible for importing myo-inositol (MI) into the cells. MI is a precursor for a family of signal transduction molecules, phosphatidylinositol and its derivatives, that regulates many cellular functions. SMIT-1 null mice died soon after birth due to respiratory failure. Lung development was not significantly affected in the SMIT-1 null mice as suggested by the normal expression of lung surfactant protein A, C, and D. Development of the peripheral nerves, including the brachial plexus, facial, vagus, and intercostal nerves, and the phrenic nerve, that innervates the diaphragm, was severely affected. All of these peripheral nerve abnormalities were corrected by prenatal MI supplement, indicating that MI is essential for the development of peripheral nerve, and that the malformation of the phrenic and other peripheral nerves that regulate breathing is likely to be the primary cause of the respiratory failure and the neonatal lethality of the SMIT-1 null mice. SMIT-1 deficiency also led to lower body weight and skeletal deformity. These abnormalities were largely corrected by prenatal maternal MI supplement, suggesting that MI is also important for other aspects of fetal development. In the adult SMIT-1 deficient mice rescued by MI supplement, MI content in their brain, kidney, skeletal muscle, liver and sciatic nerve was greatly reduced. The sciatic nerve, in particular, was most dependent on SMIT-1 for the accumulation of MI, and nerve conduction velocity and protein kinase C activity in this tissue were significantly reduced by SMIT-1 deficiency. In addition, skeletal muscle mass and ability to hang onto a wire were also affected by SMIT-1 deficiency. These data suggest that SMIT-1 is essential for neuromuscular functions. Moreover, the growth of long bone was also affected in the SMIT-1 deficient mice, indicating that SMIT-1 also plays a role in bone growth after birth. The mouse SMIT-1 gene is located at the telomeric region of mouse chromosome 16, a region syntenic to human chromosome 21q22, an extra copy of which causes Down syndrome. To investigate if SMIT-1 plays a role in Down syndrome the SMIT-1 null mutation was introduced into the Ts1Cje mice, a Down syndrome mouse model, to bring the SMIT-1 gene copy number back to two in this Down syndrome critical region (DSCR)-included trisomy mice. The DSCR-included trisomy mice with two copies of SMIT-1 gene exhibited improved growth rate and partially normalized the cerebellum/brain ratio, but had no effect on the craniofacial abnormality. The results suggest that extra copy of SMIT-1 gene might contribute to some aspects of Down syndrome. DOI: 10.5353/th_b3549606 Subjects: InositolProtein precursorsMice - PhysiologyDown syndrome

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