Date on Master's Thesis/Doctoral Dissertation


Document Type

Doctoral Dissertation

Degree Name

Ph. D.


Biochemistry and Molecular Biology

Committee Chair

Ellis, Steven R.

Author's Keywords

Diamond-Blackfan anemia; Shwachman-Diamond syndrome; Ribosomes; Marrow failure


Bone marrow--Diseases; Ribosomes


The inherited bone marrow failure syndromes (IBMFS) encompass a heterogeneous collection of rare disorders characterized by hematological abnormalities, generalized growth delays, and an increased incidence of malignant transformation. These disorders include: Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS), cartilage-hair hypoplasia (CHH), and dyskeratosis congenita (DC). Despite sharing overarching similarities, each of these disorders manifests distinct clinical phenotypes. Similar to their clinical features, the molecular underpinnings of the IBMFS have characteristics that are both shared and distinctive. Aberrations in ribosome synthesis have been associated with each of the IBMFS providing a common molecular target for pathogenic mutations in disease related genes. In some cases, the ribosome appears to be the major target of pathogenic lesions, whereas in others, effects on ribosome synthesis are secondary and appear to have a modifying influence on disease presentation. For example, the primary target of pathogenic lesions in dyskeratosis congenita is telomerase which distinguishes it from other IBMFS. The X-linked form of dyskeratosis congenita, however, affects both telomerase function and ribosome synthesis and is considerably more severe than the somatic forms of the disease that only affect telomerase. Thus, differences in primary targets of pathogenic lesions can account for the distinct clinical presentations of certain IBMFS. In other cases, where ribosome synthesis appears to be the major target of disease causing mutations, the basis for diverse clinical manifestations remains unknown. The body of work presented in this dissertation is focused on Shwachman-Diamond syndrome and Diamond-Blackfan anemia, two IBMFS where defects in ribosome synthesis appear to underlie disease pathophysiology. The approach was to use yeast models of both diseases to explore mechanisms by which ribosome synthesis was affected using the 60S ribosomal subunit as a common molecular target. My studies revealed that 60S subunit biogenesis was affected by distinct mechanisms in the two disease models and that these differences may provide the molecular underpinnings for the distinct clinical presentations observed in DBA and SDS patients. Further studies on the mechanism by which 60S subunit biogenesis was affected in the SDS model have clear implications for the treatment of this disorder.