Aesthetic outcome and the need for revision of unilateral cleft lip repair at Komfo Anokye Teaching Hospital

Background: The Millard method of unilateral cleft lip repair has been  associated with a short lip and a flattened nose on the cleft side. The aim of this study was to determine the need for revision surgery followingrepair of unilateral cleft lip repair at the Komfo Anokye Teaching HospitalMethod: Satisfaction with facial appearance (upper lip, nose and general facial appearance) was assessed quantitatively by means of a Visual Analogue Scale (VAS), where 0cm indicates totally unsatisfied or “highly unattractive” and 10cm indicates totally satisfied or “highly attractive”. Three assessors - parents, surgeon and layperson - were purposively selected to score their level of satisfaction with repair of complete and incomplete unilateral cleft lip. The assessors also indicated the need for any revision.Results: The total sample size was 120, of which 40.0% were male and 60.0% were female. There were 79 cases of repaired complete unilateral cleft lip and 41 incomplete unilateral cleft lip. Average scores of satisfactionof parents were 6.6, 6.8 and 7.2 for nose, lip and general facial  appearance (GFA) respectively. Satisfaction scores for surgeon were  6.1(nose), 6.0(lip) and 6.5(GFA), while those of the lay-assessor were5.2(nose), 5.4 (lip) and 6.0(GFA). Concerning the need for revision, parents indicated 30.2% as needing revision, surgeon 33%; and  lay-assessor 40%. Of the cases that needed revision, 33.3% were complete cleft lip and 0.1% were incomplete cleft lip.Conclusion: Parents were more satisfied with unilateral cleft lip repair using the Millard procedure than either the surgeon or lay assessor. Those who needed revision were mostly children who presented with complete unilateral cleft lip

Genome-wide profiling of p63 DNA-binding sites identifies an element that regulates gene expression during limb development in the 7q21 SHFM1 locus.

Contains fulltext : 88501.pdf (publisher's version ) (Open Access)Heterozygous mutations in p63 are associated with split hand/foot malformations (SHFM), orofacial clefting, and ectodermal abnormalities. Elucidation of the p63 gene network that includes target genes and regulatory elements may reveal new genes for other malformation disorders. We performed genome-wide DNA-binding profiling by chromatin immunoprecipitation (ChIP), followed by deep sequencing (ChIP-seq) in primary human keratinocytes, and identified potential target genes and regulatory elements controlled by p63. We show that p63 binds to an enhancer element in the SHFM1 locus on chromosome 7q and that this element controls expression of DLX6 and possibly DLX5, both of which are important for limb development. A unique micro-deletion including this enhancer element, but not the DLX5/DLX6 genes, was identified in a patient with SHFM. Our study strongly indicates disruption of a non-coding cis-regulatory element located more than 250 kb from the DLX5/DLX6 genes as a novel disease mechanism in SHFM1. These data provide a proof-of-concept that the catalogue of p63 binding sites identified in this study may be of relevance to the studies of SHFM and other congenital malformations that resemble the p63-associated phenotypes

Analysis of the robustness of network-based disease-gene prioritization methods reveals redundancy in the human interactome and functional diversity of disease-genes

Complex biological systems usually pose a trade-off between robustness and fragility where a small number of perturbations can substantially disrupt the system. Although biological systems are robust against changes in many external and internal conditions, even a single mutation can perturb the system substantially, giving rise to a pathophenotype. Recent advances in identifying and analyzing the sequential variations beneath human disorders help to comprehend a systemic view of the mechanisms underlying various disease phenotypes. Network-based disease-gene prioritization methods rank the relevance of genes in a disease under the hypothesis that genes whose proteins interact with each other tend to exhibit similar phenotypes. In this study, we have tested the robustness of several network-based disease-gene prioritization methods with respect to the perturbations of the system using various disease phenotypes from the Online Mendelian Inheritance in Man database. These perturbations have been introduced either in the protein-protein interaction network or in the set of known disease-gene associations. As the network-based disease-gene prioritization methods are based on the connectivity between known disease-gene associations, we have further used these methods to categorize the pathophenotypes with respect to the recoverability of hidden disease-genes. Our results have suggested that, in general, disease-genes are connected through multiple paths in the human interactome. Moreover, even when these paths are disturbed, network-based prioritization can reveal hidden disease-gene associations in some pathophenotypes such as breast cancer, cardiomyopathy, diabetes, leukemia, parkinson disease and obesity to a greater extend compared to the rest of the pathophenotypes tested in this study. Gene Ontology (GO) analysis highlighted the role of functional diversity for such diseases.Spanish Ministry of Science and Innovation (MICINN) FEDER BIO2011-22568 (http://www.mineco.gob.es/portal/site/mineco/); and by EU grantEraSysbio+(SHIPREC http://www.erasysbio.net/index.php?index=279) Euroinvestigación (EUI2009-04018

ZNF185 is a p63 target gene critical for epidermal differentiation and squamous cell carcinoma development.

Development and maintenance of healthy stratified epithelia require the coordination of complex transcriptional programmes. The transcription factor p63, a member of the p53 family, plays a crucial role in epithelial development and homeostasis. Analysis of the p63-dependent transcriptome indicated that one important aspect of p63 functions in epithelial development is the regulation of cell-cell and cell-matrix adhesion programmes. However, limited knowledge exists on the relevant cell-cell adhesion molecules involved in physiological epithelial formation. Similarly, limited data are available to understand if deregulation of the cell-cell adhesion programme is important in tumour formation. Here, using the epidermis as an experimental model with the RNA sequencing approach, we identify a novel p63-regulated gene induced during differentiation, ZNF185. ZNF185 is an actin-cytoskeleton-associated Lin-l 1, Isl-1 and Mec-3 (LIM) domain-containing protein, whose function is poorly known. We found that p63 binds to a specific enhancer region, promoting its expression to sustain epithelial differentiation. ZNF185 silencing strongly impaired keratinocyte differentiation according to gene array analysis. ZNF185 is detected at the cell-cell periphery where it physically interacts with E-cadherin, indicating that it is important to maintain epithelial integrity beyond its pro-differentiation role. Interestingly, poorly differentiated, including head and neck, cervical and oesophageal, squamous cell carcinomas display loss of ZNF185 expression. Together, these studies reinforce that p63 is a crucial gene for maintaining epithelial tissue integrity and support the deregulation of the cell-cell adhesion programme,which plays a critical role in carcinoma development.This work has been partially supported by AIRC Grant IG-15653 to GM. This work has been mainly supported by IDI-IRCCS (RC to EC and GM) and RF-2016-02362541 (to EC)