| First Author | Stoffel W | Year | 2019 |
| Journal | Am J Pathol | Volume | 189 |
| Issue | 9 | Pages | 1831-1845 |
| PubMed ID | 31199918 | Mgi Jnum | J:282076 |
| Mgi Id | MGI:6370102 | Doi | 10.1016/j.ajpath.2019.05.008 |
| Citation | Stoffel W, et al. (2019) Neutral Sphingomyelinase 2 (SMPD3) Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization. Am J Pathol 189(9):1831-1845 |
| abstractText | SMPD3 deficiency in the neutral sphingomyelinase (Smpd3(-/-)) mouse results in a novel form of juvenile dwarfism, suggesting smpd3 is a polygenetic determinant of body height. SMPD3 controls homeostasis of the sphingomyelin cycle in the Golgi compartment, essential for membrane remodeling, initiating multiform vesicle formation and transport in the Golgi secretory pathway. Using the unbiased Smpd3(-/-) genetic model, this study shows that the perturbed Golgi secretory pathway of chondrocytes of the epiphyseal growth zone leads to dysproteostasis, skeletal growth inhibition, malformation, and chondrodysplasia, but showed unimpaired mineralization in primary and secondary enchondral ossification centers. This has been elaborated by biochemical analyses and immunohistochemistry of long bones of Smpd3(-/-) mice. A more precise definition of the microarchitecture and three-dimensional structure of the bone was shown by peripheral quantitative computed tomography, high-resolution microcomputed tomography, and less precisely by dual-energy X-ray absorptiometry for osteodensitometry. Ablation of the Smpd3 locus as part of a 980-kb deletion on chromosome 8 in the fro/fro mutant, generated by chemical mutagenesis, is held responsible for skeletal hypomineralization, osteoporosis, and multiple fractures of long bones, which are hallmarks of human osteogenesis imperfecta. The phenotype of the genetically unbiased Smpd3(-/-) mouse, described here, precludes the proposed role of Smpd3 as a candidate gene of human osteogenesis imperfecta, but suggests SMPD3 deficiency as the pathogenetic basis of a novel form of chondrodysplasia. |
