Genetic Disruption of Anoctamin 5 in Mice Replicates Human Gnathodiaphyseal Dysplasia (GDD).

Abstract

Gnathodiaphyseal dysplasia (GDD; OMIM#166260) is a rare skeletal disorder which is mainly characterized by cemento-osseous lesions in mandibles, bone fragility, bowing and diaphyseal sclerosis of tubular bones. GDD is caused by point mutations in Anoctamin-5 (ANO5); however, the disease mechanisms remain unclear. Here we generated Ano5-knockout (KO) mice using a CRISPR/Cas 9 approach to study loss of function aspects of GDD mutations. Homozygous Ano5 knockout mice (Ano5-/-) replicate some typical traits of human GDD including massive jawbones, bowing tibia, sclerosis and cortical thickening of femoral and tibial diaphyses. Serum alkaline phosphatase (ALP) levels were elevated in Ano5-/- mice as in GDD patients. Calvaria-derived Ano5-/- osteoblast cultures show increased osteoblastogenesis, which is consistent with our previous in vitro observations. Bone matrix is hypermineralized, and the expression of bone formation-related factors is enhanced in Ano5-/- mice, suggesting that the osteogenic anomaly arises from a genetic disruption of Ano5. We believe this new mouse model will shed more light on the development of skeletal abnormalities in GDD on a cellular and molecular level.

• Authors: Xiaoyu Wang, Xiu Liu, Rui Dong, Chao Liang, Ernst J Reichenberger, Ying Hu
• Journal: Calcified tissue international (Calcif Tissue Int) Vol. 104 Issue 6 Pg. 679-689 (06 2019) ISSN: 1432-0827 [Electronic] United States
• PMID: 30712070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ANO5 protein, mouse
• Anoctamins

Topics

• Animals
• Animals, Newborn
• Anoctamins (genetics)
• Bone and Bones (pathology)
• Cells, Cultured
• Disease Models, Animal
• Female
• Gene Deletion
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Osteoblasts (pathology, physiology)
• Osteogenesis Imperfecta (genetics, pathology)
• Phenotype