The membrane-associated lipid signal phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) regulates intracellular ion channel activity, actin cytoskeletal rearrangements, including cilia tip shedding, endocytosis, and many vesicular trafficking events including cilia trafficking. Recently PI(4,5)P2 has been identified to also regulate key steps in autophagy including autophagosome lysosome fusion. PI(4,5)P2 is phosphorylated at the 3-position of the inositol ring by the phosphoinositide 3-kinase (PI3K) to generate PI(3,4,5)P3, which promotes cell migration, proliferation, metabolism and polarization. The inositol polyphosphate 5-phosphatase family of enzymes remove the D5-position phosphate from PI(4,5)P2 and PI(3,4,5)P3 to form PI(4)P and PI(3,4)P2 respectively, and these lipid phosphatases regulate PI signalling both temporally and spatially. Recent evidence has shown many 5-phosphatases when mutated result in developmental syndromes including ciliopathies. INPP5E, Synaptojannin-1 and OCRL are mutated in human syndromes that exhibit complex developmental abnormalities affecting the brain, kidneys and eyes. Recently, mutations in SKIP (INPP5K), a PI(4,5)P2 and PI(3,4,5)P3 5-phosphatase, were identified to cause a complex human syndrome including progressive muscle weakness due to muscular dystrophy, cataracts, and cognitive defects. However, the molecular basis of this INPP5K mutant syndrome is still emerging. Here we generated a murine model of INPP5K deficiency specifically in muscle. Inpp5k-/- mice were embryonic lethal at E10.5 and therefore skeletal muscle deletion of the gene was achieved in mice. Inpp5kfl/fl;MCKCre mice were born at normal Mendelian ratios, and appeared normal at birth, but by 12 weeks developed many aspects of the phenotype of the human syndrome including muscle dystrophy, muscle weakness and altered PI signalling. The molecular mechanisms by which dysregulation of PI signalling in muscle leads to muscular dystrophy will be presented.
Funding: NHMRC APP1082253