# Investigating the protective effect of maternal Thm1 heterozygosity against cleft palate

> **NIH NIH R21** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $193,750

## Abstract

PROJECT SUMMARY
Craniofacial anomalies accompany a third of all birth defects, with isolated or nonsyndromic clefts of the lip and
palate (CL/P) alone occurring in 1/700 births worldwide. These isolated CL/P have a complex etiology including
both genetic and environmental factors. Environmental factors such as folate intake and smoking have been
shown to affect maternal environment, however, maternal genetic effects have been difficult to model and study.
The objective of this proposal is to study the first-ever protective maternal genetic effect on palatogenesis. To
our knowledge, a protective maternal genetic effect in a mouse model has not been described for any birth
defect. Our data show that Specc1lDCCD2/+ and Thm1aln/+ single heterozygotes resulted in ~20% (n=45) and 0%
(n=24) CP respectively. In contrast, Specc1lDCCD2/+;Thm1aln/+ double heterozygotes showed ~33% CP (n=30).
However, this occurrence of CP was observed only when the cross was performed with Specc1lDCCD2/+ mothers.
With Thm1aln/+ mothers, the same cross resulted in 0% CP in both single (n=20) and double heterozygotes
(n=25). Since, a Specc1lDCCD2/+ male crossed with wildtype female still resulted in ~20% CP in Specc1lDCCD2/+
heterozygotes (n=20), we ruled out a negative effect by Specc1lDCCD2/+ mothers or protective effect by Thm1aln/+
fathers. Thus, we hypothesized that the Thm1aln/+ female provides a protective maternal genetic effect for CP.
We will test our hypothesis by investigating the maternal environment in Aim1 and by determining the molecular
nature of the protective effect in Aim2. The maternal environment will be evaluated by embryo transfer
experiments and generation of uterine-specific Thm1 heterozygosity. The molecular nature of the protective
effect will be determined by assessing epigenetic, trancriptomic, and proteomic changes in maternal and
embryonic tissue. Both Thm1 and Specc1l deficiency affects ciliogenesis. Thus, our cellular and molecular
studies will focus on cytoskeletal and ciliary signaling changes underlying the protective effect. These studies
will generate novel insights and testable hypotheses regarding the role of maternal environment in the etiology
of the isolated CP complex disease.

## Key facts

- **NIH application ID:** 10871838
- **Project number:** 5R21DE032515-02
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Irfan Saadi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $193,750
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871838

## Citation

> US National Institutes of Health, RePORTER application 10871838, Investigating the protective effect of maternal Thm1 heterozygosity against cleft palate (5R21DE032515-02). Retrieved via AI Analytics 2026-06-05 from https://api.ai-analytics.org/grant/nih/10871838. Licensed CC0.

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