Molecular and genetic characterization of the Sorting Nexin 10 R51Q mutation and other mutations, causing osteopetrosis in infancy in Palestinian clans

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Autosomal recessive osteopetrosis (ARO) is a severe inherited disease in infants due to aberrant bone growth caused by defects in bone resorption. ARO is a rare disease, but with high prevalence in consanguineous populations. 2012 a point mutation in the Sorting Nexin 10 (SNX10) gene was discovered in Palestinian endemic populations leading to an arginin/glutamin exchange (SNX10 R51Q). Since then different mutations in the SNX10 gene causing osteopetrosis were identified all over the world. Gold-standard treatment of ARO is the transplantation of healthy hematopoietic stem cells in order to rescue the defect of the bone resorbing osteoclasts with wild type cells. However, a successful therapy is hampered by late diagnosis of the disease and subsequent late transplantation, the unknown effect of heterozygous donor cells, a low donor chimerism upon transplantation, and unknown effects of the mutation possibly contributing to pathologies in patients after transplantation. We therefore generated a highly translational approach to unravel the etiology of ARO caused by SNX10 R51Q, by investigating population genetics, developing transgenic mouse models for the SNX10 R51Q disease and by analysing the cell biological mechanisms of osteoclast failure. In the first funding period we achieved in the first 16 months substantial progress in our trilateral interdisciplinary research consortium from Palestine, Germany and Israel. We increased awareness of the population and local government towards genetic counseling for the disease. We successfully mapped SNPs and STRs to the locus, detected new affected families and discovered so far unknown mutations in ARO. With the generation of SNX10 R51Q Knock-In mice we established the first Knock-In mouse model for an ARO mutation closely resembling the patient phenotype. We discovered a novel osteoclast phenotype that displays unlimited fusion and thus leads to non-functional resorption. This discovery points towards fundamental questions of osteoclast fusion that are still unclear but are important beyond osteopetrosis for common diseases such as osteoporosis and cancer. We now aim in a bench to bed side translation and back approach to characterize genetic frequencies of the SNX10 R51Q- and one novel mutation in the Palestine population. We will dissect the osteoclast autonomous and non-autonomous function in SNX10 R51Q Knock-In and SNX10 complete Knock-Out mice using bone marrow chimeric mouse models. These experiments will give insight in SNX10-related pathologies occuring in patients even after transplantation. And finally we will carefully analyze the molecular mechanisms of SNX10 in general and SNX10 R51Q in particular in the osteoclast fusion process and how mixed fusions of wild type cells and mutant cells affect the fusion process, a situation that might occur in patients upon transplantations. Our insights will be of direct benefit for the patients and will give implications for bone biology in general.