# Role of SPECC1L cytoskeletal protein in palate elevation dynamics

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $596,710

## Abstract

PROJECT SUMMARY
Orofacial clefts involving the lip and palate are the most common congenital craniofacial malformation that occur
as part of >400 syndromes or as an isolated phenotype in ~1/700 live-births. Non-syndromic cleft palate only by
itself afflicts 1/1700 children with a 2:1 increased incidence in females. The lifetime cost for medical treatment,
educational services, and lost productivity averages more than $100,000 per affected person. Embryonic
palatogenesis involves bilateral vertical outgrowth of shelves from the maxilla that elevate horizontally and fuse
above the tongue. While palatogenesis has been studied for more than a century, it is not clear how palatal
shelves reorient from the vertical to horizontal direction during elevation. One reason for this knowledge gap is
that this process is rapid and therefore hard to time and capture. Another is a lack of methodologies to assess
palate elevation and of mouse models with a well-characterized palate elevation delay. Our studies show that
palatal shelves elevate in less than 3 hours in utero and that there is a defined embryonic window of time for
elevation. We have also assessed the dynamic interplay of cell proliferation, cell orientation and actomyosin
contraction that underlies normal palatal shelf elevation. We have established novel methodologies to use MRI
for in utero imaging and to use finite element analysis to model palatal shelf elevation. In addition, we have been
studying the role of cytoskeletal scaffolding protein SPECC1L in palatogenesis. We identified the first de novo
autosomal dominant SPECC1L mutations in patients with orofacial clefts. We and others have now shown that
patients with SPECC1L mutations clustered in the second coil ed coil domain (CCD2) or calponin homology
domain (CHD) commonly manifest hypertelorism, cleft palate and omphalocele among other phenotypes. Using
multiple Specc1l mouse alleles, we have established that loss of SPECC1L leads to a delay in palatal shelf
elevation. Interestingly, in-frame CCD2 specific mutations (deletions, point mutations) in mice result in a more
severe palatal shelf elevation delay, indicating a gain-of-function. At the cellular level, CCD2 leads to
perinuclear mislocalization of SPECC1L along with a disruption of cytoplasmic filamentous actin and non-muscle
myosin II. Lastly, our preliminary data show that cleft palate in CCD2 mutants is rescued upon maternal folic
acid supplementation. In Aim 1, we will study the cell and tissue mechanics underlying both normal and abnormal
palate elevation in CCD2 alleles using ex vivo and in vivo magnetic resonance imaging and computational
modeling. In Aim 2, we will investigate the cellular and molecular mechanisms underlying the gain-of-function in
CCD2 mutant cells using state-of-the-art proteomic analyses. In Aim 3, we will determine how maternal folate
supplementation rescues palate elevation defects in CCD2 mutants. Successful completion of these studies will
provide cr...

## Key facts

- **NIH application ID:** 10904649
- **Project number:** 5R01DE032825-02
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Irfan Saadi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $596,710
- **Award type:** 5
- **Project period:** 2023-08-10 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904649

## Citation

> US National Institutes of Health, RePORTER application 10904649, Role of SPECC1L cytoskeletal protein in palate elevation dynamics (5R01DE032825-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10904649. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*