# Cellular and molecular characterization of LIG1 mutations causing a spectrum of primary immune deficiencies

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $204,281

## Abstract

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.

## Key facts

- **NIH application ID:** 9960430
- **Project number:** 5R21AI142144-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** CHARLOTTE CUNNINGHAM-RUNDLES
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $204,281
- **Award type:** 5
- **Project period:** 2019-06-19 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960430

## Citation

> US National Institutes of Health, RePORTER application 9960430, Cellular and molecular characterization of LIG1 mutations causing a spectrum of primary immune deficiencies (5R21AI142144-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9960430. Licensed CC0.

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