Gene datasets associated with mouse cleft palate

Abstract

This article presents data on genes associated with cleft palate (CP), retrieved through both a full-text systematic review and a mouse genome informatics (MGI) database search. In order to group CP-associated genes according to function, pathway, biological process, and cellular component, the genes were analyzed using category enrichment bioinformatics tools, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). This approach provides invaluable opportunities for the identification of candidate pathways and genes in CP research.

p63 establishes epithelial enhancers at critical craniofacial development genes

“…Many key genes required for epidermal development and epithelial lineage specification were only up-regulated in the combined system, including JAG2 , GRHL3 , and SFN (fig. S2D and table S2), and importantly, their dysregulation has been implicated in developmental malformations including skeletal dysplasias and orofacial clefting ( 29 , 35 , 36 ). In addition, the top 15 up-regulated genes (via fold change p63 + KLF4/ctrl) by the combined system include keratinocyte-specific genes (e.g., KRT6a and KRT14 ) that are key mediators of cell-cell adhesion programs (e.g., CDSN , LAD1 , and GJB4 ), as well as keratinocyte differentiation (e.g., TGM5 and FA2H ), all of which were not up-regulated when p63 was expressed without KLF4 (Fig.…”

“…Genetic Association Database studies ( 45 ) of genes up-regulated in our transdifferentiation model identified cleft lip and/or cleft palate as the most highly enriched disease-associated category (Fig. 4A), with 76 associated genes identified, including genes known to cause nsCL/P (e.g., WNT9B , JAG2 , and CDH1 ; full list in table S4B) ( 29 , 35 , 46 , 47 ). Many of these 76 genes have been identified as causal for orofacial clefting through human syndromes and family studies, while others are in proximity of SNPs involved in CL/P but are not known to be causally or functionally involved with orofacial clefting.…”

“…This could be in part due to extensive rewiring of the p63 response element network between mouse and human, as well as human-specific craniofacial enhancers that were recently reported ( 69 , 70 ). Further, mouse models of known disease-causing genes such as IRF6 , PVRL1 ( 71 ), and CDH1 ( 46 ) in human also fail to recapitulate clefting of the lip ( 15 , 16 , 35 , 44 ), suggesting stark differences in these processes between species and highlighting the need for orthogonal human approaches. In humans, GWAS and other approaches have identified 40 human risk loci for nsCL/P with conclusive evidence.…”

Allele-specific gene regulation by KDM6A

“…KDM6A targets common to both reciprocal crosses include genes such as Gdf11 and Sox11 previously implicated in development of the roof of the mouth and hard palate, malformations of which are often seen in Kabuki syndrome due to mutations in KDM6A (Bogershausen et al, 2016;Silva-Andrade et al, 2019;Yap et al, 2020). GDF11 mutations in human lead to orofacial abnormalities, while SOX11 has a role in human palatogenesis (Cox et al, 2019;Khan et al, 2018;Suzuki et al, 2018). Our findings of additional dysregulated genes may help identify other gene targets implicated in congenital defects seen in Kabuki syndrome (Bogershausen et al, 2016;Lintas and Persico, 2018).…”

Gene–environment interplay and MicroRNAs in cleft lip and cleft palate

“…Genes involved in mouse CL and/or CP have been curated through a systematic literature review and mouse genome informatics (MGI) database search. 28,29 To date, there are 55 and 252 genetically mutated mice displaying CL and CP, respectively (Table 1).…”