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Published on: July 3, 2020
Massive osteopetrosis caused by non-functional osteoclasts in R51Q SNX10 mutant mice
Merle Stein1, Maayan Barnea-Zohar2, Moran Shalev2
1Institute of Comparative Molecular Endocrinology, University of Ulm, 89081 Ulm, Germany.
Abstract:
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.
Insights
The R51Q mutation in sorting nexin 10 (SNX10) causes autosomal recessive osteopetrosis (ARO). A new mouse model confirms this SNX10 mutation leads to severe osteopetrosis and disease-like symptoms in mice.
Area of Science:
- Genetics
- Molecular Biology
- Pathology
Background:
- Sorting nexin 10 (SNX10) mutations, specifically R51Q, are linked to autosomal recessive osteopetrosis (ARO) in humans.
- ARO is a rare genetic disorder characterized by defective osteoclast function, leading to bone overgrowth and impaired bone remodeling.
Purpose of the Study:
- To create and characterize the first R51Q SNX10 knock-in mouse model.
- To investigate the pathological mechanisms underlying ARO caused by the R51Q SNX10 mutation.
Main Methods:
- Generation of a knock-in mouse model with the specific R51Q mutation in the SNX10 gene.
- Phenotypic analysis of homozygous mutant mice, including growth, survival, dental development, and bone structure.
- Assessment of osteoclast function, focusing on ruffled border formation and proton secretion.
Main Results:
- Homozygous R51Q SNX10 mutant mice display severe, early-onset, and widespread osteopetrosis.
- Mutant mice exhibit key features of human ARO, such as stunted growth, failure to thrive, dental abnormalities, osteomyelitis, and reduced lifespan.
- Osteopetrosis in this model is attributed to osteoclast inactivity, characterized by absent ruffled borders and impaired proton secretion.
Conclusions:
- The R51Q mutation in SNX10 is confirmed as a causative factor for autosomal recessive osteopetrosis.
- This R51Q SNX10 knock-in mouse model effectively recapitulates human ARO and serves as a valuable tool for studying the disease.
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