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Genotype-Phenotype Predictions in Rare Genetic Diseases: The Relationship between Glycine Decarboxylase Mutations and Non-Ketotic Hyperglycinemia Severity
There are over 7000 known rare diseases, many of which have a genetic etiology. While each individual disease is rare, approximately 1 in 10 people suffer from a rare disease. The majority of these diseases are under-researched because the potential impact of research on each individual disease is considered small, but there is an extremely high unmet need for research that will yield treatments as only approximately 400 of the 7000 rare disease have an FDA approved treatment.
Monogenic defects that alter metabolism may cause complex pathological states including neurological diseases that show a wide range of symptoms such as, seizures, epilepsy, neuropathy, cerebral defects and movement disorders. While these defects occur in only one gene, often large number of mutations are observed in the patient population leading to a broad range of phenotypes which complicate the study of such defects. For example, all 30 of the known disorders of amino acid metabolism have dozens of known causative mutations. Thus, these diseases are in acute need of new tools for rapid genotype-phenotype assessment to aid model development to and treatment testing. But the study of these defects also affords a unique opportunity to understand the relationship between genotype and phenotype in a monogenic system.
One such defect occurs in Glycine Decarboxylase (GLDC), which cleaves glycine in the first step of the mitochondrial glycine cleavage system (GCS). Glycine cleavage yields the formation of 5,10-methylene THF, a key intermediate in folate biosynthesis and one-carbon metabolism which is utilized to synthesize nucleotides and proteins and thus broadly impacts cellular homeostasis. Known perturbations of glycine cleavage are associated with cancers, pluripotency, and host susceptibility to viral infection. They are also involved in neural tube defects (NTDs) and the rare disorder non-ketotic hyperglycinemia (NKH) . The hundreds of mutations in GLDC that give rise to NKH disease, present a unique system to investigate how these mutations underlie NKH, as well as provide models for a broader understanding of functional annotation of mutations in hundreds of monogenic disorders at cellular and organismal levels.
History
Date Modified
2021-08-08Defense Date
2021-06-23CIP Code
- 26.0102
Research Director(s)
Kasturi HaldarCommittee Members
Siyuan Zhang Zachary Schafer Athanasia PanopoulosDegree
- Doctor of Philosophy
Degree Level
- Doctoral Dissertation
Alternate Identifier
1262767299Library Record
6103407OCLC Number
1262767299Additional Groups
- Biological Sciences
- Integrated Biomedical Sciences
Program Name
- Integrated Biomedical Sciences