DLX4 is associated with orofacial clefting and abnormal jaw development.

Cleft lip and/or palate (CL/P) are common structural birth defects in humans. We used exome sequencing to study a patient with bilateral CL/P and identified a single nucleotide deletion in the patient and her similarly affected son­c.546_546delG, predicting p.Gln183Argfs*57 in the Distal-less 4 (DLX4) gene. The sequence variant was absent from databases, predicted to be deleterious and was verified by Sanger sequencing. In mammals, there are three Dlx homeobox clusters with closely located gene pairs (Dlx1/Dlx2, Dlx3/Dlx4, Dlx5/Dlx6). In situ hybridization showed that Dlx4 was expressed in the mesenchyme of the murine palatal shelves at E12.5, prior to palate closure. Wild-type human DLX4, but not mutant DLX4_c.546delG, could activate two murine Dlx conserved regulatory elements, implying that the mutation caused haploinsufficiency. We showed that reduced DLX4 expression after short interfering RNA treatment in a human cell line resulted in significant up-regulation of DLX3, DLX5 and DLX6, with reduced expression of DLX2 and significant up-regulation of BMP4, although the increased BMP4 expression was demonstrated only in HeLa cells. We used antisense morpholino oligonucleotides to target the orthologous Danio rerio gene, dlx4b, and found reduced cranial size and abnormal cartilaginous elements. We sequenced DLX4 in 155 patients with non-syndromic CL/P and CP, but observed no sequence variants. From the published literature, Dlx1/Dlx2 double homozygous null mice and Dlx5 homozygous null mice both have clefts of the secondary palate. This first finding of a DLX4 mutation in a family with CL/P establishes DLX4 as a potential cause of human clefts.

5.2 Ethics, equity and global responsibilities in oral health and disease.

The charge of this Section is ethics and global responsibilities in oral health and disease. Oral health is determined by the same factors as those for general health. To a limited extent, the level of oral health care and dental education. The philosophy and organization of the health care system and dental education, therefore, are key determinants of oral health. Dental education has expanded in many countries where there has been an increase in wealth. Unfortunately, there has been no concomitant increase in the number of dental educators. This is a problem throughout the world. This present situation raises certain ethical issues with regard to professional responsibilities. It also raises some important questions for dental education. This Section has chosen to focus its efforts on examining two issues: * What can be done within dental schools? * What can be done external to dental schools - either individually or collectively? The best practices identified are more akin to goals, as it is recognized that, in a world in which there are enormous variations in economic, environmental, social, and cultural features, a single uniform set of practices is impracticable. The central core value identified is the realization by students, and faculty/teaching staff of the quest of life-long learning against a background of the social and ethical responsibilities of health professionals. The conclusion of the group is that biology is not the sole determinant of health. Understanding the role of social, economic, environmental and other factors in determining health status is critical if greater equity in dental education and care are to be achieved.