Cleft lip with or without cleft palate (CLP) is one of the most common birth defects in man with an incidence of between 1 in 700 and 1 in 1000 live births worldwide. Considerable progress has been made over the last few decades to determine the genes responsible for syndromic forms of CLP and genome-wide association studies have implicated many genomic regions (and candidate genes) in the genetic contribution to non-syndromic CLP. However, for a substantial fraction of cleft cases, the underlying genetic basis remains unknown. In addition, much of the focus on cleft gene functions has been on the few transcriptional regulators and growth factors that have been implicated, largely ignoring the many other causative genes. He we pursue new findings from two known CLP proteins, IRF6 and MID1, that suggest a convergence of function around the direct regulation of epithelial cell-cell adhesion during lip morphogenesis. The project investigates the newly discovered linkages that each of these proteins have with processes responsible for coordinating the dynamic behavior of intercellular adhesion complexes with the underlying changes in the cellular cytoskeleton that ultimately facilitate morphogenesis of the lip. In addition, we provide further support for the importance of components of this specific regulatory complex by investigating the direct functional impact of likely pathogenic variants recently discovered in a cohort of large multigenerational families with non-syndromic CLP. The project is highlighted not just by the unique insight into the molecular mechanisms underlying CLP that the research plan offers, but also the various novel and state-of-the-art approaches used to pursue the work aimed at understanding the causes of this common birth defect.

Public Health Relevance

We have identified previously unknown functions for two proteins for which deficiency causes prominent syndromic forms of cleft lip with or without cleft palate (CLP). Together with new CLP candidates identified from exome sequencing of a large international cohort of multigenerational families with non-syndromic CLP, we have identified a likely major role for a complex that regulates the dynamic behavior of the embryonic facial epithelia that is required for correct fusion of the early facial tissues to form the upper lip. Understanding the molecular and cellular mechanisms responsible for CLP is vital not only to help identify other genes that contribute to the incidence of CLP but also to help develop possible interventional therapies to one day either prevent or minimize the severity of presentation in patients to improve their quality of life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE027879-03
Application #
10103808
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Stein, Kathryn K
Project Start
2019-03-01
Project End
2024-02-29
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Missouri Kansas City
Department
Type
Schools of Dentistry/Oral Hygn
DUNS #
010989619
City
Kansas City
State
MO
Country
United States
Zip Code
64110