Biochemical Consequences of Cdkal1 Mutations that Result in Unprocessed, Nonfunctional Insulin and Type 2 Diabetes
Abstract
In recent years, studies have associated human individual genetic differences with some of the most devastating diseases, but have also led to early, life-saving, and prolonging preventative measures. The association of brca 1 and 2 with breast cancer is the best known example. Many times these studies focus on mutations called single nucleotide polymorphisms (SNPs) and whether or not they are associated with an increased risk for a particular disease like diabetes, coronary heart disease, rheumatoid arthritis, or bipolar disorder. A gene called Cdkal1 has recently been recognized as a high-risk assessment gene for Type 2 Diabetes (T2D). T2D, sometimes referred to as adult-onset diabetes, is the most common form of diabetes, affecting over 200 million people worldwide and is a chronic condition affecting how a person s body metabolizes a sugar called glucose. Proper glucose metabolism is dependent on insulin, a peptide hormone produced in the pancreas. In T2D, the pancreas is not able to make enough insulin to properly metabolize glucose and glucose builds up in the blood. Insulin is first made as a larger molecule called pre-proinsulin that is precisely shortened to form proinsulin. Proinsulin must be precisely shortened again to generate useable insulin. If proinsulin is not cut or incorrectly cut, then it is not useable. Cdkal1 helps make sure that the cutting site is made properly so that useable insulin can be formed. When mutations of Cdkal1 occur on both copies of a person s chromosomes, there is a 1.50 risk of T2D. This is comparable to the brca1 and 2 risks, 2.0, for breast cancer. Yet, we do not understand how mutations of Cdkal1 impact the production, processing, and availability of insulin. The key to understanding lies with the function of the Cdkal1 gene product and its importance to insuring the correct synthesis of pre-proinsulin. The Cdkal1 gene product, the Cdkal1 protein, is among a large family of proteins involved in making critical changes to a type of ribonucleic acid known as transfer RNA or tRNA. tRNAs decode genetic information into proteins, i.e., they decode the genetic information for pre-proinsulin in the pancreas into the pre-proinsulin protein. tRNAs insert the correct amino acid at the absolutely correct position of this and other proteins during protein synthesis. The critical change that Cdkal1 makes in tRNA enables the tRNA to perform this function accurately. The Cdkal1 protein uniquely modifies just one of the ~45 human tRNAs, tRNALys3, that inserts the amino acid lysine at just the right position in insulin. This is very important to proper insulin production. If Cdkal1 is mutated and cannot properly modify tRNALys3, then pre-proinsulin could be incorrectly synthesized in the pancreas. The improperly synthesized pre-proinsulin would not be precisely shortened to proinsulin and then to insulin. Thus, mutations in Cdkal1 are an intriguing cause of T2D that reside outside of the insulin gene. The aims of this proposal are driven by the hypothesis that in patients with Cdkal1-associated T2D pancreatic tRNALys3 lacks the critical modification made by the Cdkal1 protein, resulting in a pre-proinsulin that cannot be shortened properly to proinsulin and then to functional insulin. Based on this hypothesis, we propose specific aims: (1) Understand how the lack of a functioning Cdkal1, and thus a missing modification of human tRNALys3, critically affects translation and the subsequent processing of insulin precursors. (2) Gain insight into the mechanism of Cdkal1 function, the modification of human tRNALys3. Therefore, this work is focused on understanding a distinctive form of T2D, Cdkal1-associated T2D and development of Cdkal1 as a biomarker to identify and monitor at-risk individuals and assess treatment response. This project will reveal how mutation of Cdkal1 leads to T2D by understanding the interaction between Cdkal1 and tRNALys3, the effect of a missing tR
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610428
Entities
People
- Kyla Frohlich
Organizations
- State University of New York at Albany
- United States Army