Associations between laterality of orofacial clefts and medical and academic outcomes.

Patients with oral clefts have an increased risk of other malformations, syndromes, and lower academic performance in school. Few studies have investigated if laterality of clefts is associated with medical and academic outcomes. Oral clefts have nonrandom laterality, with left-sided clefts occurring approximately twice as often as right-sided clefts. Using a retrospective study design, we examined potential associations of cleft attributes and outcomes in patients with cleft lip with or without cleft palate (CL/P) born in 2003-2010 who were treated at the Seattle Children's Craniofacial Center. The following variables were extracted from medical records: cleft type, medical history, maternal hyperglycemia, other malformations, and the need for academic support at school. We used logistic regression to examine risk of associations with outcomes of interest. Relative to patients with left-sided clefts, patients with bilateral CL/P were more likely to have a syndrome. Patients with nonsyndromic right-sided CL/P had a higher risk (OR and 95%CI: 3.5, 1.3-9.5, and 5.5, 1.9-16.0, respectively) of having other malformations and requiring academic support at school, when compared to patients with left-sided CL/P. Understanding the etiology of oral clefts is complicated, in part because both genetic and environmental factors contribute to the risk of developing a cleft. However, the different outcomes associated with cleft laterality suggest that right-sided clefts may have a distinct etiology. Using laterality to study cleft subgroups may advance our understanding of the etiology of this common birth defect.

Subclassification of the RBCC/TRIM superfamily reveals a novel motif necessary for microtubule binding.

The biological significance of RBCC (N-terminal RING finger/B-box/coiled coil) proteins is increasingly being appreciated following demonstrated roles in disease pathogenesis, tumorigenesis, and retroviral protective activity. Found in all multicellular eukaryotes, RBCC proteins are involved in a vast array of intracellular functions; but as a general rule, they appear to function as part of large protein complexes and possess ubiquitin-protein isopeptide ligase activity. Those members characterized to date have diverse C-terminal domain compositions and equally diverse subcellular localizations and functions. Using a bioinformatics approach, we have identified some new RBCC proteins that help define a subfamily that shares an identical domain arrangement (MID1, MID2, TRIM9, TNL, TRIM36, and TRIFIC). Significantly, we show that all analyzed members of this subfamily associate with the microtubule cytoskeleton, suggesting that subcellular compartmentalization is determined by the unique domain architecture, which may in turn reflect basic functional similarities. We also report a new motif called the COS box, which is found within these proteins, the MURF family, and a distantly related non-RBCC microtubule-binding protein. Notably, we demonstrate that mutations in the COS box abolish microtubule binding ability, whereas its incorporation into a nonmicrotubule-binding RBCC protein redirects it to microtubule structures. Further bioinformatics investigation permitted subclassification of the entire human RBCC complement into nine subfamilies based on their varied C-terminal domain compositions. This classification schema may aid the understanding of the molecular function of members of each subgroup and their potential involvement in both basic cellular processes and human disease.

Expression of three spalt (sal) gene homologues in zebrafish embryos.

Three homologues of the Drosophilaregion-specific homeotic gene spalt (sal) have been isolated in zebrafish, sall1a, sall1b and sall3. Phylogenetic analysis of these genes against known salDNA sequences showed zebrafish sall1aand sall1b to be orthologous to other vertebrate sal-1 genes and zebrafish sall3to be orthologous to other vertebrate sal-3 genes, except Xenopus sall3. Phylogenetic reconstruction suggests that zebrafish sall1a and sall1bresulted from a gene duplication event occurring prior to the divergence of the ray-finned and lobe-finned fish lineages. Analysis of the expression pattern of the zebrafish sal genes shows that sall1a and sall3 share expression domains with both orthologous and non-orthologous vertebrate sal genes. Both are expressed in various regions of the CNS, including in primary motor neurons. Outside of the CNS, sall1a expression is observed in the otic vesicle (ear), heart and in a discrete region of the pronephric ducts. These analyses indicate that orthologies between zebrafish sal genes and other vertebrate sal genes do not imply equivalence of expression pattern and, therefore, that biological functions are not entirely conserved. However we suggest that, like other vertebrate sal genes, zebrafish sal genes have a role in neural development. Also, expression of zebrafish sall1a in the otic vesicle, heart sac and the pronephric ducts of zebrafish embryos is possibly consistent with some of the abnormalities seen in Sall1-deficient mice and in Townes-Brocks Syndrome, a human disorder which is caused by mutations in the human spalt gene SALL1.