A subset of intellectual disability cases in humans are caused by mutations in an X-linked gene essential for a quality control mechanism called nonsense-mediated RNA decay (NMD). Patients with mutations in this gene—UPF3B—commonly have not only ID, but also schizophrenia, autism, and attention-deficit/hyperactivity disorder. Thus, the study of UPF3B and NMD may provide insight into a wide spectrum of cognitive and psychological disorders. To examine how mutations in UPF3B can cause mental defects, we will generate and characterize induced-pluripotent stem cells from intellectual disability patients with mutations in the UPF3B gene. In addition to having a role in neural development, our recent evidence suggests that NMD is important for maintaining the identity of ES cells and progenitor cells. How does NMD do this? While NMD is a quality control mechanism, it is also a well characterized biochemical pathway that serves to rapidly degrade specific subsets of normal messenger ribonucleic acids (mRNAs), the transiently produced copies of our genetic material: deoxyribonucleic acid (DNA). We have obtained evidence that NMD preferentially degrades mRNAs that interfere with the stem cell program (i.e., NMD promotes the decay mRNAs encoding proteins that promote differentiation and inhibit cell proliferation). In this proposal, we will identify the target mRNAs of NMD in stem and progenitor cells and directly address the role of NMD in maintaining the stem-like state.
iPS cells provide a means to elucidate the mechanisms underlying diseases that afflict a growing number of Californians. Our proposed project concerns making and testing iPS cells from patients with mutations in the UPF3B gene, all of whom have intellectual disabilities. In addition, many of these patients have autism, attention-deficit disorders, and schizophrenia. By using iPS cells to identify the cellular and molecular defects in these patients, we have the potential to ultimately ameliorate the symptoms of many of these patients. This is important, as over 1.6 million people in California have serious mental illness. Moreover, a large proportion of patients with UPF3B mutations have autism, a disorder that has undergone an alarming 12-fold increase in California between 1987 and 2007.
The public mental health facilities in California are inadequate to meet the needs of people with mental health disorders. Furthermore, what is provided is expensive: $4.4 billion was spent on public mental health agency services in California in 2006. Mental health problems also exert a heavy burden on California’s criminal justice system. In 2006, over 11,000 children and 40,000 adults with mental health disorders were incarcerated in California’s juvenile justice system.
Our research is also directed towards understanding fundamental mechanisms by which all stem cells are maintained, which has the potential to also impact non-psychiatric disorders suffered by Californians.
This application proposes to study the role of nonsense-mediated RNA decay (NMD), a cellular pathway and quality-control mechanism, in the maintenance of self-renewal and pluripotency. There are three Specific Aims: (1) to identify mRNA targets of NMD in human stem and progenitor cells; (2) to determine the function of NMD in human stem and progenitor cells, with a focus on self-renewal; and (3) to study induced pluripotent stem cells (iPSCs) from patients with mutations in an NMD pathway gene that cause a range of cognitive and psychiatric disabilities, including autism.
Significance and Innovation
- The proposal is innovative. NMD is an important, broadly conserved cellular mechanism that has not been well studied in human stem cells.
- The applicantís hypothesis concerning the role of NMD in stem cell self-renewal and pluripotency is novel and interesting.
- The proposal could have both broad significance for stem cell biology and specific significance for human intellectual disabilities and neurodevelopmental disorders, including autism, that have been associated with mutations in an NMD pathway gene.
Feasibility and Experimental Design
- The experimental design is thorough and the research plan is feasible.
- The preliminary data describing gain- and loss-of-function studies are very strong and support the hypothesis that NMD genes may play important roles in cellular differentiation.
- The preliminary data in human stem cells are not as strong and the gene expression differences observed are not particularly large.
Principal Investigator (PI) and Research Team
- The PI has published extensively in the field of NMD and is eminently qualified to conduct the proposed research.
- The assembled research team is very strong.
- The team does not have a great deal of experience with human cells but reviewers did not view this as a major problem.
Responsiveness to the RFA
- The proposal is responsive to the RFA as it uses human cells.