Nonsyndromic cleft lip and palate: CRISPLD genes and the folate gene pathway connection.
BACKGROUND
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.


METHODS
Single nucleotide polymorphisms (SNPs) in CRISPLD1 were genotyped in our non-Hispanic white and Hispanic multiplex and simplex NSCLP families.


RESULTS
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).


CONCLUSIONS
These novel findings suggest that CRISPLD1 plays a role in NSCLP through the interaction with CRISPLD2 and folate pathway genes.
Department of Pediatrics, University of Texas Medical School, Houston, TX 77030, USA.
Brett T
BT
Chiquet
Robin
R
Henry
Amber
A
Burt
John B
JB
Mulliken
Samuel
S
Stal
Susan H
SH
Blanton
Jacqueline T
JT
Hecht
D015815:Cell Adhesion Molecules / Q000235:genetics*; D002971:Cleft Lip / Q000150:complications* / Q000208:ethnology / Q000235:genetics; D002972:Cleft Palate / Q000150:complications* / Q000208:ethnology / Q000235:genetics; D005492:Folic Acid / Q000378:metabolism*; D005796:Genes / Q000235:genetics* / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
C525599:CRISPLD2 protein, human; D015815:Cell Adhesion Molecules; D050835:Interferon Regulatory Factors; D005492:Folic Acid
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