Regulatory variant in<i><scp>FZD</scp>6</i>gene contributes to nonsyndromic cleft lip and palate in an African‐American family

Cvjetkovic, Nevena; Maili, Lorena; Weymouth, Katelyn S.; Hashmi, S. Shahrukh; Mulliken, John B.; Topczewski, Jacek; Letra, Ariadne; Yuan, Qiuping; Blanton, Susan H.; Swindell, Eric C.; Hecht, Jacqueline

doi:10.1002/mgg3.155

Cited by 25 publications

(25 citation statements)

References 82 publications

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“…We hypothesized that additional RVs in this region are associated with bIMT. Indeed, our candidate gene re-sequencing study, as well as other recent studies, have shown that sequencing regions under linkage peaks can successfully identify RVs influencing complex traits and disorders[16,22–25], particularly in extended families. Extended families are well-suited for the identification of RVs for several reasons including: 1) Pedigrees may be enriched for individual RVs, making them easier to study[26,27] and 2) Co-segregation of an RV with the trait can be examined to help differentiate between causal and non-causal RVs[26,27].…”

Section: Introductionmentioning

confidence: 73%

Rare Variants in NOD1 Associated with Carotid Bifurcation Intima-Media Thickness in Dominican Republic Families

et al. 2016

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Cardiovascular disorders including ischemic stroke (IS) and myocardial infarction (MI) are heritable; however, few replicated loci have been identified. One strategy to identify loci influencing these complex disorders is to study subclinical phenotypes, such as carotid bifurcation intima-media thickness (bIMT). We have previously shown bIMT to be heritable and found evidence for linkage and association with common variants on chromosome 7p for bIMT. In this study, we aimed to characterize contributions of rare variants (RVs) in 7p to bIMT. To achieve this aim, we sequenced the 1 LOD unit down region on 7p in nine extended families from the Dominican Republic (DR) with strong evidence for linkage to bIMT. We then performed the family-based sequence kernel association test (famSKAT) on genes within the 7p region. Analyses were restricted to single nucleotide variants (SNVs) with population based minor allele frequency (MAF) <5%. We first analyzed all exonic RVs and then the subset of only non-synonymous RVs. There were 68 genes in our analyses. Nucleotide-binding oligomerization domain (NOD1) was the most significantly associated gene when analyzing exonic RVs (famSKAT p = 9.2x10-4; number of SNVs = 14). We achieved suggestive replication of NOD1 in an independent sample of twelve extended families from the DR (p = 0.055). Our study provides suggestive statistical evidence for a role of rare variants in NOD1 in bIMT. Studies in mice have shown Nod1 to play a role in heart function and atherosclerosis, providing biologic plausibility for a role in bIMT thus making NOD1 an excellent bIMT candidate.

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Section: Introductionmentioning

confidence: 73%

Rare Variants in NOD1 Associated with Carotid Bifurcation Intima-Media Thickness in Dominican Republic Families

et al. 2016

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“…For instance, López Rodríguez et al identified SNPs in a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells [31]. For NSCL/P, Cvjetkovic et al identified an SNP in intron 1 of FZD6 that creates an allele-specific protein-binding site and decreases promoter activity, which is involved in craniofacial development and contributes to NSCL/P by perturbing the WNT signaling pathway [18]. Before the GWAS of NSCL/P, the NTN1 gene in the chromosome 17p13 region was not associated with NSCL/P susceptibility.…”

Section: Discussionmentioning

confidence: 99%

The functional variant of NTN1 contributes to the risk of nonsyndromic cleft lip with or without cleft palate

Zhu

Lou

et al. 2019

Eur J Hum Genet

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Previous genome-wide association study of nonsyndromic cleft lip with or without cleft palate (NSCL/P) identified a susceptible variant (rs4791774). We hypothesized that the functional single nucleotide polymorphism (SNP) may be in linkage disequilibrium with this lead SNP. The potential functional SNP (rs4791331) was identified by bioinformatic analysis. A case-control study with 891 orofacial cleft cases and 830 controls was designed to investigate its association with orofacial cleft. The allele-specific DNA-protein binding preference was predicted by JASPAR database. Cell proliferation, cycle and apoptosis, luciferase activity and netrin-1 (NTN1) expression were examined after transfection with the rs4791331 C/T vector in HEK-293 and HEPM cell lines. Forty-six lip tissues of NSCL/P patients were collected to detect NTN1 expression. ntn1a knockout zebrafish models were generated by CRISPR/Cas9 and observed with micro-CT. In the case-control study, the rs4791331-T allele was associated with an increased risk of nonsyndromic orofacial cleft (OR = 1.41, 95% CI = 1.19-1.68), as well as the subgroups cleft lip only (OR = 1.46, 95% CI = 1.14-1.87) and cleft lip and palate (OR = 1.58, 95% CI = 1.27-1.96). The T allele of rs4791331 exhibited anti-apoptotic effects and promoted cell cycle progression at the G1/S transition. Decreased enhancer activity and reduced NTN1 expression following transfection of the T allele were observed. Carriers of the CT/TT genotypes showed significantly lower expression of NTN1 than CC carriers. The ntn1a −/− zebrafish showed relatively wider intermaxillary fissures. These results indicate that rs4791331 (C > T) disrupted motif binding and led to abnormal expression of NTN1, which may be involved in the development of NSCL/P. These authors contributed equally:

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“…1d). MMP2 and FOS have previously been shown to interact in studies that demonstrate that the inhibition of MMP2 suppresses the induction of c-FOS and both of these genes are activated in metastatic gastric adenocarcinoma [13,63]. FOS, which has been shown to play a role in cellular functions including apoptosis, is a target for CASP8 [64].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Crispld2 in zebrafish identifies a novel network for nonsyndromic cleft lip with or without cleft palate candidate genes

et al. 2018

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Orofacial development is a multifaceted process involving tightly regulated genetic signaling networks, that when perturbed, lead to orofacial abnormalities including cleft lip and/or cleft palate. We and others have shown an association between the cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2) gene and nonsyndromic cleft lip with or without cleft palate (NSCLP). Further, we demonstrated that knockdown of Crispld2 in zebrafish alters neural crest cell migration patterns resulting in abnormal jaw and palate development. In this study, we performed RNA profiling in zebrafish embryos and identified 249 differentially expressed genes following knockdown of Crispld2. In silico pathway analysis identified a network of seven genes previously implicated in orofacial development for which differential expression was validated in three of the seven genes (CASP8, FOS, and MMP2). Single nucleotide variant (SNV) genotyping of these three genes revealed significant associations between NSCLP and FOS/rs1046117 (GRCh38 chr14:g.75746690 T > C, p = 0.0005) in our nonHispanic white (NHW) families and MMP2/rs243836 (GRCh38 chr16:g.55534236 G > A; p = 0.002) in our Hispanic families. Nominal association was found between NSCLP and CASP8/rs3769825 (GRCh38 chr2:g.202111380 C > A; p < 0.007). Overtransmission of MMP2 haplotypes were identified in the Hispanic families (p < 0.002). Significant gene-gene interactions were identified for FOS-MMP2 in the NHW families and for CASP8-FOS in the NHW simplex family subgroup (p < 0.004). Additional in silico analysis revealed a novel gene regulatory network including five of these newly identified and 23 previously reported NSCLP genes. Our results demonstrate that animal models of orofacial clefting can be powerful tools to identify novel candidate genes and gene regulatory networks underlying NSCLP.

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Regulatory variant inFZD6gene contributes to nonsyndromic cleft lip and palate in an African‐American family

Cited by 25 publications

References 82 publications

Rare Variants in NOD1 Associated with Carotid Bifurcation Intima-Media Thickness in Dominican Republic Families

Rare Variants in NOD1 Associated with Carotid Bifurcation Intima-Media Thickness in Dominican Republic Families

The functional variant of NTN1 contributes to the risk of nonsyndromic cleft lip with or without cleft palate

Knockdown of Crispld2 in zebrafish identifies a novel network for nonsyndromic cleft lip with or without cleft palate candidate genes

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