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PLoS Genet. 2017 Jan 5;13(1):e1006552. doi: 10.1371/journal.pgen.1006552. eCollection 2017 Jan.

SBDS-Deficient Cells Have an Altered Homeostatic Equilibrium due to Translational Inefficiency Which Explains their Reduced Fitness and Provides a Logical Framework for Intervention.

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INGM, National Institute of Molecular Genetics, "Romeo ed Enrica Invernizzi", Milan, Italy.
DiSIT, University of Eastern Piedmont, Alessandria, Italy.
School of Biosciences, University of Birmingham Edgbaston Birmingham, United Kingdom.
Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Telethon Institute of Genetics and Medicine (TIGEM)-Fondazione Telethon, Pozzuoli, Italy.
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
SickKids Children Hospital, Toronto, Ontario, Canada.
DBS, Università degli Studi di Milano, Milan, Italy.


Ribosomopathies are a family of inherited disorders caused by mutations in genes necessary for ribosomal function. Shwachman-Diamond Bodian Syndrome (SDS) is an autosomal recessive disease caused, in most patients, by mutations of the SBDS gene. SBDS is a protein required for the maturation of 60S ribosomes. SDS patients present exocrine pancreatic insufficiency, neutropenia, chronic infections, and skeletal abnormalities. Later in life, patients are prone to myelodisplastic syndrome and acute myeloid leukemia (AML). It is unknown why patients develop AML and which cellular alterations are directly due to the loss of the SBDS protein. Here we derived mouse embryonic fibroblast lines from an SbdsR126T/R126T mouse model. After their immortalization, we reconstituted them by adding wild type Sbds. We then performed a comprehensive analysis of cellular functions including colony formation, translational and transcriptional RNA-seq, stress and drug sensitivity. We show that: 1. Mutant Sbds causes a reduction in cellular clonogenic capability and oncogene-induced transformation. 2. Mutant Sbds causes a marked increase in immature 60S subunits, limited impact on mRNA specific initiation of translation, but reduced global protein synthesis capability. 3. Chronic loss of SBDS activity leads to a rewiring of gene expression with reduced ribosomal capability, but increased lysosomal and catabolic activity. 4. Consistently with the gene signature, we found that SBDS loss causes a reduction in ATP and lactate levels, and increased susceptibility to DNA damage. Combining our data, we conclude that a cell-specific fragile phenotype occurs when SBDS protein drops below a threshold level, and propose a new interpretation of the disease.

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