TY - JOUR
T1 - Massive osteopetrosis caused by non-functional osteoclasts in R51Q SNX10 mutant mice
AU - Stein, Merle
AU - Barnea-Zohar, Maayan
AU - Shalev, Moran
AU - Arman, Esther
AU - Brenner, Ori
AU - Winograd-Katz, Sabina
AU - Gerstung, Jennifer
AU - Thalji, Fadi
AU - Kanaan, Moien
AU - Elinav, Hila
AU - Stepensky, Polina
AU - Geiger, Benny
AU - Tuckermann, Jan
AU - Elson, Ari
N1 - We thank Dr. Timothy Dahlem and the University of Utah Mutation Generation and Detection Core Facility for reagents. We also thank Dr. Rebecca Haffner-Kraus, Ms. Golda Damari, Dr. Alina Berkovitz, and Ms. Sima Peretz of the Weizmann Institute's Transgenic and Knockout Core Facility for help in preparing the mouse models used in this study; Ms. Ofira Higfa, Mr. Neriah Sharabi and Mr. Thomas Neidlinger for expert animal care in the central animal facilities of the Weizmann Institute and Ulm University; and Dr. Elena Kartvelishvily, Dr. Smadar Zaidman, Ms. Ilana Sabanay, and Dr. Ifat Kaplan-Ashiri of the Weizmann Institute's Chemical Research Support Department for assistance with electron microscopy studies. We also thank Prof. Memet Aker for discussions at the start of this project. AE is the incumbent of the Marshall and Renette Ezralow Professorial Chair. BG is the Erwin Neter Professor in Cell and Tumor Biology. Funding: This study was supported by the Trilateral DFG (Tu220/12) grant awarded to JT, AE and BG, by the DFG CRC Trauma grant (SFB1149) to JT, and by grants from the Kekst Family Institute for Medical Genetics and the David and Fella Shapell Center for Genetic Disorders Research, both of the Weizmann Institute, to AE. The agencies that supported this study were not involved in any aspect of conducting this study or in its publication. Author contributions: Merle Stein, Mayaan Barnea-Zohar, Moran Shalev: Investigation, visualization. Esther Arman: Methodology. Ori Brenner: Investigation, visualization. Sabina Winograd-Katz, Jennifer Gerstung: Investigation. Fadi Thalji, Moien Kanaan: Conceptualization, funding acquisition. Hila Elinav, Polina Stepensky: Resources. Benjamin Geiger, Jan Tuckermann, Ari Elson: Conceptualization, validation, writing (original, review, editing), supervision, project administration, and funding acquisition. These authors contributed equally to this study: Merle Stein, Maayan Barnea-Zohar.
PY - 2020/7
Y1 - 2020/7
N2 - The R51Q mutation in sorting nexin 10 (SNX10) was shown to cause a lethal genetic disease in humans, namely autosomal recessive osteopetrosis (ARO). We describe here the first R51Q SNX10 knock-in mouse model and show that mice homozygous for this mutation exhibit massive, early-onset, and widespread osteopetrosis. The mutant mice exhibit multiple additional characteristics of the corresponding human disease, including stunted growth, failure to thrive, missing or impacted teeth, occasional osteomyelitis, and a significantly-reduced lifespan. Osteopetrosis in this model is the result of osteoclast inactivity that, in turn, is caused by absence of ruffled borders in the mutant osteoclasts and by their inability to secrete protons. These results confirm that the R51Q mutation in SNX10 is a causative factor in ARO and provide a model system for studying this rare disease.
AB - The R51Q mutation in sorting nexin 10 (SNX10) was shown to cause a lethal genetic disease in humans, namely autosomal recessive osteopetrosis (ARO). We describe here the first R51Q SNX10 knock-in mouse model and show that mice homozygous for this mutation exhibit massive, early-onset, and widespread osteopetrosis. The mutant mice exhibit multiple additional characteristics of the corresponding human disease, including stunted growth, failure to thrive, missing or impacted teeth, occasional osteomyelitis, and a significantly-reduced lifespan. Osteopetrosis in this model is the result of osteoclast inactivity that, in turn, is caused by absence of ruffled borders in the mutant osteoclasts and by their inability to secrete protons. These results confirm that the R51Q mutation in SNX10 is a causative factor in ARO and provide a model system for studying this rare disease.
U2 - https://doi.org/10.1016/j.bone.2020.115360
DO - https://doi.org/10.1016/j.bone.2020.115360
M3 - مقالة
SN - 8756-3282
VL - 136
JO - Bone
JF - Bone
M1 - 115360
ER -