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Scube 3 – a mouse model for Paget disease of bone?

Skeletal phenotypes of newborn wild type (A, C, E, G) and Scube3N294K/N294K (B, D, F, H) mice.

The vertebrate Scube (Signal peptide, CUB and EGF-like domain-containing protein) family consists of three independent members Scube1-3, which encode secreted cell surface-associated membrane glycoproteins. Little is known about the general function of this gene family, and the roles of the family members during adulthood. However, one major function appears to be in bone development and homeostasis and another one in neurological functions.

The new mutant mouse line presented by Fuchs and colleagues carries a missense mutation in exon 8 of the Scube3 gene (Scube3N294K/N294K). To better understand the Scube3 gene function the mutant mouse line was phenotypically characterized in the German Mouse Clinic (GMC). Scube3N294K/N294K mutants showed morphological abnormalities of the skeleton, alterations of parameters relevant for bone metabolism, changes in renal function and hearing impairments. These findings correlate with characteristics of the rare metabolic bone disorder Paget disease of bone (PDB), associated with the chromosomal region of human SCUBE3. PDB1 is characterized by focal areas of increased bone turnover. Human SCUBE3 was originally identified following transcriptional profiling of vascular endothelial cells and demonstrated significant enrichment in primary osteoblasts and long bones.
In addition, in Scube3N294K/N294K mice alterations in energy metabolism, behavior and neurological functions were detected.

The Scube3N294K/N294K mutant mouse line may serve as a new model for further studying the effect of impaired SCUBE3 gene function.

Fuchs H, Sabrautzki S, Przemeck GK, Leuchtenberger S, Lorenz-Depiereux B, Becker L, Rathkolb B, Horsch M, Garrett L, Östereicher MA, Hans W, Abe K, Sagawa N, Rozman J, Vargas-Panesso IL, Sandholzer M, Lisse TS, Adler T, Aguilar-Pimentel JA, Calzada-Wack J, Ehrhard N, Elvert R, Gau C, Hölter SM, Micklich K, Moreth K, Prehn C, Puk O, Racz I, Stoeger C, Vernaleken A, Michel D, Diener S, Wieland T, Adamski J, Bekeredjian R, Busch DH, Favor J, Graw J, Klingenspor M, Lengger C, Maier H, Neff F, Ollert M, Stoeger T, Yildirim AÖ, Strom TM, Zimmer A, Wolf E, Wurst W, Klopstock T, Bekers J, Gailus-Durner V, Hrabé de Angelis M. The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations. G3 (Bethesda). 2016 Dec 7;6(12):4035-4046. doi: 10.1534/g3.116.033670.