Massive osteopetrosis caused by non-functional osteoclasts in R51Q SNX10 mutant mice

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...

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Published inBone (New York, N.Y.) Vol. 136; p. 115360
Main Authors 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
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.07.2020
Subjects
Animals
Autosomal recessive osteopetrosis
Mice
Mutation - genetics
Osteoclast
Osteoclasts
Osteopetrosis
Osteopetrosis - diagnostic imaging
Osteopetrosis - genetics
SNX10
Sorting nexin 10
Sorting Nexins - genetics
Autosomal recessive osteopetrosis
RANKL
M-CSF
PTH
CTX
P1NP
RQ/RQ
Osteoclast
SNX10
RANK
+
Osteopetrosis
OB
Sorting nexin 10
OCL
HSCT
ARO
RQ
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Summary: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. •Homozygous R51Q SNX10 mice are severely osteopetrotic due to osteoclast inactivity.•Mutant osteoclasts lack ruffled borders and cannot secrete protons.•R51Q SNX10 mice model key aspects of autosomal recessive osteopetrosis in man.
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ISSN:8756-3282
1873-2763
DOI:10.1016/j.bone.2020.115360