The goal of this proposal is to determine the underlying mechanism of LIG1 syndrome, a heterogeneous primary immune deficiency (PID). Until recently only a single individual was found to have compound heterozygous mutations in LIG1, and the disease etiology was confirmed with biochemical and cellular studies. Recently we have identified identified new alleles of LIG1 that also impact DNA ligase activity. DNA LIG1 is essential for DNA replication during normal cell development, and therefore a connection between ligase deficiency and PID would be expected; what was not expected was the clinical heterogeneity that was observed. We observe biochemical defects of these LIG1 clinical alleles, which suggest models for the clinical heterogeneity. We propose to screen additional patients for new variants in LIG1 or associated DNA replication genes, and to investigate the biochemical and cellular consequences of the most common variants that are predicted to impact ligase function. These studies will find similarities between different alleles that allow patients to be grouped together or identify sub-groups of patients whose disease and treatments may progress differently. As LIG1 is important for DNA replication and repair in all cells, identification of this cohort will provide the opportunity to test additional hypotheses such as the sensitivity to DNA damaging agents or elevated cancer risk, as was exhibited by the first diagnosed individual. As a previous mouse model does not phenocopy the human immune deficiency of LIG1 mutation, we will also develop appropriate cell culture models to study the cellular impacts of LIG1 mutations.

Public Health Relevance

These studies will identify new disease alleles that cause primary immune deficiency and study their cellular and biochemical consequences. Completion of the project will lead to deeper understanding of how the immune system normally functions, and advance the diagnosis of individuals with risk of primary immune deficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI142144-01A1
Application #
9824627
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Voulgaropoulou, Frosso
Project Start
2019-06-19
Project End
2021-05-31
Budget Start
2019-06-19
Budget End
2020-05-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109