Inherited Bone Marrow Failure syndromes (IBMFS) are a heterogeneous class of diseases that converge on very few subjects. They are unified by a block in maturation of one or multiple blood lineages, are genetically inherited, and have an increased incidence of cancers and myelodisplastic syndromes. Several IBMFSs have been linked to defects in ribosome biogenesis. Diamond Blackfan anemia (DBA) which presents with a macrocytic anemia has 10 known affected genes all of which encode structural proteins of the large or small ribosomal subunit. In contrast, there is only a single gene known to be involved in the pathogenesis of Shwachman Diamond Syndrome (SDS) which usually presents as exocrine pancreatic insufficiency along with neutropenia. Investigation of DBA pathogenesis lead to the knowledge that deficiency of certain ribosomal proteins leads to a specific defect in ribosomal pre-RNA processing. In this work, we have identified a new DBA gene, RPL31, by isolating mononuclear cells from the patient’s blood and subsequently harvesting total RNA used for Northern blotting to identify delays in pre-rRNA processing in both this patient as well as those found in a patient with other large subunit DBA mutations. Additionally, we have created a human cell model of SDS that has allowed us to explore changes in respiration originally shown in yeast models. To this end, we have identified increases in reactive oxygen species, changes in oxygen consumption, mitochondrial membrane potential, and cell cycle delay, all linked to depletion of SBDS protein.
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Molecular bases of inherited bone marrow failures : Shwachman-Diamond syndrome and Diamond Blackfan anemia.
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