Molekulare und genetische Charakterisierung der Sorting Nexin 10 R51Q-Mutation und anderer Mutationen, Auslöser von Osteopetrose in palästinensischen Sippen
Zusammenfassung der Projektergebnisse
Osteoclast rich osteopetrosis is a severe disease, retarding growth and development developing after birth and requires hematopoeitic stem cell transfer as only possible potential cure. Few mutations of this monogenic disease had been characterized. This consortium aimed to characterize the most recent identified candidate gene encoding for SNX10 in the founder populations in Palestine. Assembling German, Isreal and Palestine scientists we enrolled a strong translational program to investigate the genetic basis, the cellular mechanisms the physiological characteristics in pre-clinical mouse models and finally also triggering genetic counselling in the affected Palestine clans to sensitize for the risk of consanguineous marriages. We generated a unique mouse model carrying the SNX10R51Q mutation as well a knockout allele in mice. We characterized their phenotype as osteopetrosis by state-of-the-art analysis including micro computer tomography, bone histomorphometry and gene expression analysis. We discovered ectopic formation of tooth anlagen and a decreased bone formation, but mainly a lack of resorption activity of osteoclasts. We demonstrated that part of the SNX10 defects included failure of ruffled border formation in osteoclasts, but more strikingly and stunningly, a failure to terminate fusion. The latter was characterized in detail and revealed that altered membrane trafficking led to the constant fusion of mature osteoclasts which are normally prevented to further fuse. We demonstrated enlarged osteoclasts in vivo by state-of-theart imaging and are still continuing to characterize the precise molecular mechanism of SNX10 function the fusion process of osteoclasts. We have strong evidence that the SNX10R51Q mutation comprises a loss of function due to less stability of the protein a largely phenocopy in the SNX10 knockout mice. We mapped the mutation and charachterized associated SNPs in the affected patients and their non-symptomatic heterozygous relatives and thus established a particular haplotype, that however varied to affected patients in families outside of the Karama village. The populations were also enlarged from the initial population of the Karma village to other locations of the Westbank. The project lead to multiple interactions between the different research groups and impacted on the young scientists. It also prompted an international meeting on osteoclasts organized by the PIs and the establishment of an Osteoclast Working Group in the pre-congresses of the European Calcified Tissue Society. The project gave us insights to a rare disease, but also to cell biology in general, i.e. that fusion must be terminated, a concept that is radically novel to cell biology.
Projektbezogene Publikationen (Auswahl)
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Phosphorylation of the phosphatase PTPROt at Tyr 399 is a molecular switch that controls osteoclast activity and bone mass in vivo. Science Signaling, 12(563).
Roth, Lee; Wakim, Jean; Wasserman, Elad; Shalev, Moran; Arman, Esther; Stein, Merle; Brumfeld, Vlad; Sagum, Cari A.; Bedford, Mark T.; Tuckermann, Jan & Elson, Ari
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Massive osteopetrosis caused by non-functional osteoclasts in R51Q SNX10 mutant mice. Bone, 136, 115360.
Stein, Merle; Barnea-Zohar, Maayan; Shalev, Moran; Arman, Esther; Brenner, Ori; Winograd-Katz, Sabina; Gerstung, Jennifer; Thalji, Fadi; Kanaan, Moien; Elinav, Hila; Stepensky, Polina; Geiger, Benjamin; Tuckermann, Jan & Elson, Ari
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An SNX10-dependent mechanism downregulates fusion between mature osteoclasts. Journal of Cell Science, 134(9).
Barnea-Zohar, Maayan; Winograd-Katz, Sabina E.; Shalev, Moran; Arman, Esther; Reuven, Nina; Roth, Lee; Golani, Ofra; Stein, Merle; Thalji, Fadi; Kanaan, Moien; Tuckermann, Jan; Geiger, Benjamin & Elson, Ari
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PTPRJ promotes osteoclast maturation and activity by inhibiting Cbl‐mediated ubiquitination of NFATc1 in late osteoclastogenesis. The FEBS Journal, 288(15), 4702-4723.
Shalev, Moran; Arman, Esther; Stein, Merle; Cohen‐Sharir, Yael; Brumfeld, Vlad; Kapishnikov, Sergey; Royal, Isabelle; Tuckermann, Jan & Elson, Ari
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Sorting Nexin 10 as a Key Regulator of Membrane Trafficking in Bone-Resorbing Osteoclasts: Lessons Learned From Osteopetrosis. Frontiers in Cell and Developmental Biology, 9.
Elson, Ari; Stein, Merle; Rabie, Grace; Barnea-Zohar, Maayan; Winograd-Katz, Sabina; Reuven, Nina; Shalev, Moran; Sekeres, Juraj; Kanaan, Moien; Tuckermann, Jan & Geiger, Benjamin
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SNX10 regulates osteoclastogenic cell fusion and osteoclast size in mice. Journal of Bone and Mineral Research, 39(10), 1503-1517.
Barnea-Zohar, Maayan; Stein, Merle; Reuven, Nina; Winograd-Katz, Sabina; Lee, Sooyeon; Addadi, Yoseph; Arman, Esther; Tuckermann, Jan; Geiger, Benjamin & Elson, Ari
