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1: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4512-7. Epub 2007 Mar 6.

Impaired FGF signaling contributes to cleft lip and palate.

Riley BM, Mansilla MA, Ma J, Daack-Hirsch S, Maher BS, Raffensperger LM, Russo
ET, Vieira AR, Dodé C, Mohammadi M, Marazita ML, Murray JC.

Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.

Nonsyndromic cleft lip and palate (NS CLP) is a complex birth defect resulting
from a combination of genetic and environmental factors. Several members of the
FGF and FGFR families are expressed during craniofacial development and can
rarely harbor mutations that result in human clefting syndromes. We hypothesized 
that disruptions in this pathway might also contribute to NS CLP. We sequenced
the coding regions and performed association testing on 12 genes (FGFR1, FGFR2,
FGFR3, FGF2, FGF3, FGF4, FGF7, FGF8, FGF9, FGF10, FGF18, and NUDT6) and used
protein structure analyses to predict the function of amino acid variants. Seven 
likely disease-causing mutations were identified, including: one nonsense
mutation (R609X) in FGFR1, a de novo missense mutation (D73H) in FGF8, and other 
missense variants in FGFR1, FGFR2, and FGFR3. Structural analysis of FGFR1,
FGFR2, and FGF8 variants suggests that these mutations would impair the function 
of the proteins, albeit through different mechanisms. Genotyping of SNPs in the
genes found associations between NS CLP and SNPs in FGF3, FGF7, FGF10, FGF18, and
FGFR1. The data suggest that the FGF signaling pathway may contribute to as much 
as 3-5% of NS CLP and will be a consideration in the clinical management of CLP.

PMID: 17360555 [PubMed - indexed for MEDLINE]

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