This work was supported by grant R01-DE011931 from the National Institutes of Health to J.T.H. and T32-DE015355–05 to B.T.C.
Nonsyndromic cleft lip and palate: CRISPLD genes and the folate gene pathway connection†
Article first published online: 15 NOV 2010
Copyright © 2010 Wiley-Liss, Inc.
Birth Defects Research Part A: Clinical and Molecular Teratology
Volume 91, Issue 1, pages 44–49, January 2011
How to Cite
Chiquet, B. T., Henry, R., Burt, A., Mulliken, J. B., Stal, S., Blanton, S. H. and Hecht, J. T. (2011), Nonsyndromic cleft lip and palate: CRISPLD genes and the folate gene pathway connection. Birth Defects Research Part A: Clinical and Molecular Teratology, 91: 44–49. doi: 10.1002/bdra.20737
- Issue published online: 19 JAN 2011
- Article first published online: 15 NOV 2010
- Manuscript Accepted: 5 AUG 2010
- Manuscript Revised: 19 JUL 2010
- Manuscript Received: 13 MAY 2010
- cleft lip and palate;
Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect that has a multifactorial etiology. Despite having substantial genetic liability, <15% of the genetic contribution to NSCLP has been delineated. In our efforts to dissect the genetics of NSCLP, we found that variation in the CRISPLD2 (cysteine-rich secretory protein LCCL domain containing 2) gene is associated with NSCLP and that the protein is expressed in the developing murine craniofacies. In addition, we found suggestive linkage of NSCLP (LOD > 1.0) to the chromosomal region on 8q13.2–21.13 that contains the CRISPLD1 gene. The protein products of both CRISPLD1 and CRISPLD2 contain more cysteine residues than comparably sized proteins. Interestingly, the folic acid pathway produces endogenous cysteines, and variation in genes in this pathway is associated with NSCLP. Based on these observations, we hypothesized that variation in CRISPLD1 contributes to NSCLP and that both CRISPLD genes interact with each other and genes in the folic acid pathway.
Single nucleotide polymorphisms (SNPs) in CRISPLD1 were genotyped in our non-Hispanic white and Hispanic multiplex and simplex NSCLP families.
There was little evidence for a role of variation for CRISPLD1 alone in NSCLP. However, interactions were detected between CRISPLD1/CRISPLD2 SNPs and variation in folate pathway genes. Altered transmission of one CRISPLD1 SNP was detected in the NHW simplex families. Importantly, interactions were detected between SNPs in CRISPLD1 and CRISPLD2 (15 interactions, 0.0031 ≤p < 0.05).
These novel findings suggest that CRISPLD1 plays a role in NSCLP through the interaction with CRISPLD2 and folate pathway genes. Birth Defects Research (Part A), 2011. © 2010 Wiley-Liss, Inc.