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Originally published online as doi:10.2353/ajpath.2007.061285 on April 26, 2007

Published online before print April 26, 2007
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(American Journal of Pathology. 2007;171:153-161.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061285

Neutral Sphingomyelinase (SMPD3) Deficiency Causes a Novel Form of Chondrodysplasia and Dwarfism That Is Rescued by Col2A1-Driven smpd3 Transgene Expression

Wilhelm Stoffel*, Britta Jenke, Barbara Holz, Erika Binczek, Robert Heinz Günter, Jutta Knifka{dagger}, Jürgen Koebke{dagger} and Anja Niehoff{ddagger}

From the Laboratory of Molecular Neurosciences,* Center of Molecular Medicine Cologne, Center of Biochemistry, Cologne; the Center of Anatomy,{dagger} Faculty of Medicine, University of Cologne, Cologne; and the Institute of Biomechanics and Orthopaedics,{ddagger} Deutsche Sporthoch-schule Köln, Cologne, Germany

Neutral sphingomyelinase SMPD3 (nSMase2), a sphingomyelin phosphodiesterase, resides in the Golgi apparatus and is ubiquitously expressed. Gene ablation of smpd3 causes a generalized prolongation of the cell cycle that leads to late embryonic and juvenile hypoplasia because of the SMPD3 deficiency in hypothalamic neurosecretory neurons. We show here that this novel form of combined pituitary hormone deficiency is characterized by the perturbation of the hypothalamus-pituitary growth axis, associated with retarded chondrocyte development and enchondral ossification in the epiphyseal growth plate. To study the contribution by combined pituitary hormone deficiency and by the local SMPD3 deficiency in the epiphyseal growth plate to the skeletal phenotype, we introduced the full-length smpd3 cDNA transgene under the control of the chondrocyte-specific promoter Col2a1. A complete rescue of the smpd3–/– mouse from severe short-limbed skeletal dysplasia was achieved. The smpd3–/– mouse shares its dwarf and chondrodysplasia phenotype with the most common form of human achondrodysplasia, linked to the fibroblast-growth-factor receptor 3 locus, not linked to deficits in the hypothalamic-pituitary epiphyseal growth plate axis. The rescue of smpd3 in vivo has implications for future research into dwarfism and, particularly, growth and development of the skeletal system and for current screening and future treatment of combined dwarfism and chondrodysplasia.






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Copyright © 2007 by the American Society for Investigative Pathology.