Correction: Characterization of Subtle Brain Abnormalities in a Mouse Model of Hedgehog Pathway Antagonist-Induced Cleft Lip and Palate
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PROVIDER: S-EPMC4143314 | biostudies-literature | 2014 Jan
REPOSITORIES: biostudies-literature
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Project description:Subtle behavioral and cognitive deficits have been documented in patient cohorts with orofacial clefts (OFCs). Recent neuroimaging studies argue that these traits are associated with structural brain abnormalities but have been limited to adolescent and adult populations where brain plasticity during infancy and childhood may be a confounding factor. Here, we employed high resolution magnetic resonance microscopy to examine primary brain morphology in a mouse model of OFCs. Transient in utero exposure to the Hedgehog (Hh) signaling pathway antagonist cyclopamine resulted in a spectrum of facial dysmorphology, including unilateral and bilateral cleft lip and palate, cleft of the secondary palate only, and a non-cleft phenotype marked by midfacial hypoplasia. Relative to controls, cyclopamine-exposed fetuses exhibited volumetric differences in several brain regions, including hypoplasia of the pituitary gland and olfactory bulbs, hyperplasia of the forebrain septal region, and expansion of the third ventricle. However, in affected fetuses the corpus callosum was intact and normal division of the forebrain was observed. This argues that temporally-specific Hh signaling perturbation can result in typical appearing OFCs in the absence of holoprosencephaly--a condition classically associated with Hh pathway inhibition and frequently co-occurring with OFCs. Supporting the premise that some forms of OFCs co-occur with subtle brain malformations, these results provide a possible ontological basis for traits identified in clinical populations. They also argue in favor of future investigations into genetic and/or environmental modulation of the Hh pathway in the etiopathogenesis of orofacial clefting.
| S-EPMC4105496 | biostudies-literature
Project description:The Hedgehog (Hh) signaling pathway mediates multiple spatiotemporally-specific aspects of brain and face development. Genetic and chemical disruptions of the pathway are known to result in an array of structural malformations, including holoprosencephaly (HPE), clefts of the lip with or without cleft palate (CL/P), and clefts of the secondary palate only (CPO). Here, we examined patterns of dysmorphology caused by acute, stage-specific Hh signaling inhibition. Timed-pregnant wildtype C57BL/6J mice were administered a single dose of the potent pathway antagonist vismodegib at discrete time points between gestational day (GD) 7.0 and 10.0, an interval approximately corresponding to the 15th to 24th days of human gestation. The resultant pattern of facial and brain dysmorphology was dependent upon stage of exposure. Insult between GD7.0 and GD8.25 resulted in HPE, with peak incidence following exposure at GD7.5. Unilateral clefts of the lip extending into the primary palate were also observed, with peak incidence following exposure at GD8.875. Insult between GD9.0 and GD10.0 resulted in CPO and forelimb abnormalities. We have previously demonstrated that Hh antagonist-induced cleft lip results from deficiency of the medial nasal process and show here that CPO is associated with reduced growth of the maxillary-derived palatal shelves. By defining the critical periods for the induction of HPE, CL/P, and CPO with fine temporal resolution, these results provide a mechanism by which Hh pathway disruption can result in "non-syndromic" orofacial clefting, or HPE with or without co-occurring clefts. This study also establishes a novel and tractable mouse model of human craniofacial malformations using a single dose of a commercially available and pathway-specific drug.
| S-EPMC4368540 | biostudies-literature
Project description: Not available
| S-EPMC11548905 | biostudies-literature
Project description:BackgroundNonsyndromic cleft lip with or without cleft palate (NSCLP) is a common complex birth defect. Periconceptional supplementation with folic acid, a key component in DNA synthesis and cell division, has reduced the birth prevalence of neural tube defects and may similarly reduce the birth prevalence of other complex birth defects including NSCLP. Past studies investigating the role of two common methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs), C677T (rs1801133) and A1298C (rs1801131), in NSCLP have produced conflicting results. Most studies of folate pathway genes have been limited in scope, as few genes/SNPs have been interrogated. Here, we asked whether variations in a more comprehensive group of folate pathway genes were associated with NSCLP, and were there detectable interactions between these genes and environmental exposures?MethodsFourteen folate metabolism-related genes were interrogated using 89 SNPs in multiplex and simplex non-Hispanic white and Hispanic NSCLP families.ResultsEvidence for a risk association between NSCLP and SNPs in NOS3 and TYMS was detected in the non-Hispanic white group, whereas associations with MTR, BHMT2, MTHFS, and SLC19A1 were detected in the Hispanic group. Evidence for over-transmission of haplotypes and gene interactions in the methionine arm was detected.ConclusionsThese results suggest that perturbations of the genes in the folate pathway may contribute to NSCLP. There was evidence for an interaction between several SNPs and maternal smoking, and for one SNP with gender of the offspring. These results provide support for other studies that suggest that high maternal homocysteine levels may contribute to NSCLP and should be further investigated.
| S-EPMC4098909 | biostudies-literature
Project description:The Hedgehog (Hh) pathway provides inductive signals critical for developmental patterning of the brain and face. In humans and in animal models interference with this pathway yields birth defects, among the most well-studied of which fall within the holoprosencephaly (HPE) spectrum.Timed-pregnant C57Bl/6J mice were treated with the natural Hh signaling antagonist cyclopamine by subcutaneous infusion from gestational day (GD) 8.25 to 9.5, or with a potent cyclopamine analog, AZ75, administered by oral gavage at GD 8.5. Subsequent embryonic morphogenesis and fetal central nervous system (CNS) phenotype were respectively investigated by scanning electron microscopy and high resolution magnetic resonance imaging (MRI).In utero Hh signaling antagonist exposure induced a spectrum of craniofacial and brain malformations. Cyclopamine exposure caused lateral cleft lip and palate (CLP) defects attributable to embryonic deficiency of midline and lower medial nasal prominence tissue. The CLP phenotype was accompanied by olfactory bulb hypoplasia and anterior pituitary aplasia, but otherwise grossly normal brain morphology. AZ75 exposure caused alobar and semilobar HPE with associated median facial deficiencies. An intermediate phenotype of median CLP was produced infrequently by both drug administration regimens.The results of this study suggest that interference with Hh signaling should be considered in the CLP differential and highlight the occurrence of CNS defects that are expected to be present in a cohort of patients having CLP. This work also illustrates the utility of fetal MRI-based analyses and establishes a novel mouse model for teratogen-induced CLP.
| S-EPMC2922848 | biostudies-literature
Project description:The objective of this research was to identify potential biological pathways associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and to explore the potential biological mechanisms underlying these associated pathways on risk of NSCL/P. This project was based on the dataset of a previously published genome-wide association (GWA) study on NSCL/P (Beaty et al. 2010). Case-parent trios used here originated from an international consortium (The Gene, Environment Association Studies consortium, GENEVA) formed in 2007. A total of 5,742 individuals from 1,908 CL/P case-parents trios (1,591 complete trios and 317 incomplete trios where one parent was missing) were collected and genotyped using the Illumina Human610-Quad array. Candidate pathways were selected using a list of 356 genes that may be related to oral clefts. In total, 42 candidate pathways, which included 1,564 genes and 40,208 SNPs were tested. Using a pathway-based analysis approach proposed by Wang et al (2007), we conducted a permutation-based test to assess the statistical significance of the nominal p-values of 42 candidate pathways. The analysis revealed several pathways yielding nominally significant p-values. However, controlling for the family wise error rate, none of these pathways could retain statistical significance. Nominal p-values of these pathways were concentrated at the lower tail of the distribution, with more than expected low p-values. A permutation based test for examining this type of distribution pattern yielded an overall p-value of 0.029. Thus, while this pathway-based analysis did not yield a clear significant result for any particular pathway, we conclude that one or more of the genes and pathways considered here likely do play a role in oral clefting.
| S-EPMC3404742 | biostudies-literature
Project description:Orofacial clefts are common birth defects and can occur as isolated, nonsyndromic events or as part of Mendelian syndromes. There is substantial phenotypic diversity in individuals with these birth defects and their family members: from subclinical phenotypes to associated syndromic features that is mirrored by the many genes that contribute to the etiology of these disorders. Identification of these genes and loci has been the result of decades of research using multiple genetic approaches. Significant progress has been made recently due to advances in sequencing and genotyping technologies, primarily through the use of whole exome sequencing and genome-wide association studies. Future progress will hinge on identifying functional variants, investigation of pathway and other interactions, and inclusion of phenotypic and ethnic diversity in studies.
| S-EPMC3925974 | biostudies-literature
Project description:Nonsyndromic cleft lip and palate (NSCLP) is one of the most common craniofacial anomalies in humans, affecting more than 135,000 newborns worldwide. NSCLP has a multifactorial etiology with more than 50 genes postulated to play an etiologic role. The genetic pathway comprised of Pbx-Wnt-p63-Irf6 genes was shown to control facial morphogenesis in mice and proposed as a regulatory pathway for NSCLP. Based on these findings, we investigated whether variation in PBX1, PBX2, and TP63, and their proposed interactions were associated with NSCLP. Fourteen single nucleotide variants (SNVs) in/nearby PBX1, PBX2, and TP63 were genotyped in 780 NSCLP families of nonHispanic white (NHW) and Hispanic ethnicities. Family-based association tests were performed for individual SNVs stratified by ethnicity and family history of NSCLP. Gene-gene interactions were also tested. A significant association was found for PBX2 rs3131300 and NSCLP in combined Hispanic families (p = .003) while nominal association was found for TP63 rs9332461 in multiplex Hispanic families (p = .005). Significant haplotype associations were observed for PBX2 in NHW (p = .0002) and Hispanic families (p = .003), and for TP63 in multiplex Hispanic families (.003). An independent case-control group was used to validate findings, and significant associations were found with PBX1 rs6426870 (p = .007) and TP63 rs9332461 (p = .03). Gene-gene interactions were detected between PBX1/PBX2/TP63 with IRF6 in NHW families, and between PBX1 with WNT9B in both NHW and Hispanic families (p < .0018). This study provides the first evidence for a role of PBX1 and PBX2, additional evidence for the role of TP63, and support for the proposed PBX-WNT-TP63-IRF6 regulatory pathway in the etiology of NSCLP.
| S-EPMC7325739 | biostudies-literature
Project description:Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22-q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22-q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22-q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E - 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E - 13) and rs4460498 (P = 6.51E - 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5' and 3' of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies.
| S-EPMC2778374 | biostudies-literature
Project description:The decision for lip revision surgery in patients with repaired cleft lip/palate is based on surgeons' subjective evaluation of lip disability. An objective evaluation would be highly beneficial for the assessment of surgical outcomes. In this study, the effects of lip revision on circumoral movements were objectively quantified. The hypothesis was that lip revision increases scarring and impairment. The study was a non-randomized clinical trial that included patients with cleft lip who had revision, patients with cleft lip who did not, and non-cleft control individuals. Three-dimensional facial movements were measured. Revision patients were measured before and after surgery. Other individuals were measured at similar intervals. Regression models were fit to summary measurements, and changes were modeled. Patients with repaired cleft lip/palate had fewer mean movements than control individuals. Lip revision did not worsen mean movements; however, individual patients' movements varied from 'improvement' to 'no change' to 'worse' relative to those of control individuals.
| S-EPMC2967701 | biostudies-literature