Loss of the Mouse Ortholog of the Shwachman-Diamond Syndrome Gene (Sbds) Results in Early Embryonic Lethality

Abstract

Mutations in SBDS are responsible for Shwachman-Diamond syndrome (SDS), a disorder with clinical features of exocrine pancreatic insufficiency, bone marrow failure, and skeletal abnormalities. SBDS is a highly conserved protein whose function remains largely unknown. We identified and investigated the expression pattern of the murine ortholog. Variation in levels was observed, but Sbds was found to be expressed in all embryonic stages and most adult tissues. Higher expression levels were associated with rapid proliferation. A targeted disruption of Sbds was generated in order to understand the consequences of its loss in an in vivo model. Consistent with recessive disease inheritance for SDS, Sbds^+/− mice have normal phenotypes, indistinguishable from those of their wild-type littermates. However, the development of Sbds^−/− embryos arrests prior to embryonic day 6.5, with muted epiblast formation leading to early lethality. This finding is consistent with the absence of patients who are homozygous for early truncating mutations. Sbds is an essential gene for early mammalian development, with an expression pattern consistent with a critical role in cell proliferation.

Supplemental material for this article may be found at http://mcb.asm.org/.

We thank D. Sinasac and A. Nagy for advice on the generation of the mouse model, J. Rossant and P. Georgiades for advice and probes for the analysis of early embryos, and N. Richards and G. R. B. Boocock for generating and evaluating the anti-SBDS antibody.

This work was supported by grants MT-15074 from the Canadian Institutes of Health Research (CIHR) and HL79573 from the National Institutes of Health. S.Z. is a recipient of a studentship from the CIHR-University of Toronto Training Program in Molecular Medicine. J.M.R. is a member of the Canadian Genetic Diseases Network.