Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common complex birth disorder that affects 1/700 live births, with 4000 cases each year in the United States. The etiology of NSCLP is not completely understood, but both genetics and environmental influences are known to be involved. An estimated 12-25% of the genetic variation causing NSCLP has been identified. We have recently shown that a novel gene, CRISPLD2, is associated with NSCLP and expressed in the orofacial region of developing mouse embryos at the time of lip and palate formation. We hypothesize that CRISPLD2 plays an important role during craniofacial development and that variation in this gene may cause NSCLP. Little information is known about this novel gene. The goal of this project is to characterize the role of this gene in normal craniofacial development and and how it contributes to NSCLP. To accomplish this goal, the CRISPLD2 sequence will be interrogated for variation. Identified sequence variants will be assessed for predicted function using computer algorithms and then analyzed in vitro to determine the effect on normal gene function. This paradigm has proven successful in identifying causative variants in other complex human diseases (i.e., Hirschsprung disease) and other NSCLP genes (i.e., Msx1), and will be followed to identify CRISPLD2 sequence variants with a potential biologic function. In order to determine CRISPLD2 function in normal vertebrate development, a conditional construct will be used to knock out CRISPLD2 in a mouse. Mouse models have proven useful in studying gene functions of other clefting genes (i.e., WntQb, IRF6 and Msx1). These studies are important first steps to characterize this novel craniofacial gene. This research will help us gain a better understanding craniofacial development and the causes of NSCLP. This project meets the goals of the NIDCR in improving oral health through research, research training and the dissemination of health information. Patients with NSCLP face a significant healthcare burden from surgical, dental and speech therapies. The information gained from this project will identify the function of the new clefting gene, CRISPLD2, that we recently identified and define the changes in the gene that may contribute to NSCLP. This will aid in the understanding of normal facial development, help to better diagnose and counsel families at risk for having a child with a cleft, and may lead to therapeutic intervention of orofacial clefting. ? ? ?
| Yuan, Qiuping; Chiquet, Brett T; Devault, Laura et al. (2012) Craniofacial abnormalities result from knock down of nonsyndromic clefting gene, crispld2, in zebrafish. Genesis 50:871-81 |
| Chiquet, Brett T; Hashmi, Syed S; Henry, Robin et al. (2009) Genomic screening identifies novel linkages and provides further evidence for a role of MYH9 in nonsyndromic cleft lip and palate. Eur J Hum Genet 17:195-204 |
