Functional characterization of ectodysplasin-1 and identification of novel candidate genes for ectodermal dysplasias and associated clinical features.

摘要

Ectodermal dysplasias (ED) are a group of developmental disorders in which ectodermally derived structures are abnormally formed or absent entirely. The molecular signaling pathway controlling the differentiation of ectodermal appendages has been well documented in recent years. However, questions remain concerning the key signaling molecule of this pathway, ectodysplasin-1 (EDA), the identity of the EDA signaling pathway's target genes, and the presence of additional phenotypes observed in some patients.;Despite the intensive study of EDA in recent years, the functional significance of the N-terminal intracellular domain of ectodysplasin-1 (N-EDA) has remained elusive. The yeast two-hybrid system was employed to further the understanding of this domain in the EDA protein. RBM39 has been identified as a potential interacting protein with N-EDA. Fluorescence microscopy has also demonstrated that these proteins co-localize to the nucleus, a novel finding for N-EDA.;In an attempt to identify additional genes involved in the EDA pathway that may be responsible for ED phenotypes, the translocation breakpoint regions of a patient with a chromosomal translocation t(1;6) and clinical features of ED with mild mental retardation (MR) have been partially mapped. Candidate genes have been identified near both translocation breakpoint regions.;Finally, an additional clinical feature found in some ED patients is MR of varying severity. To help understand the etiology of MR in one ED patient with a 9p subtelomeric aberration, positional cloning was used to identify DOCK8 as the potential causative gene for the MR phenotype. These results were supported by the identification of a second patient with MR in which a 9p subtelomeric deletion also disrupts DOCK8. The findings of this study indicate that haploinsufficiency of DOCK8 is likely responsible for the MR in these two patients and suggest a putative role for DOCK8 in brain development and function.;The differentiation of ectodermal appendages is a complex process in which mutations in genes at any step of EDA signaling can result in ED phenotypes. These studies contribute to the understanding of how ectodermally derived structures form, both through the discovery of novel functions for N-EDA and the identification of a new candidate target gene involved in the EDA signaling pathway. Finally, these results also provide possible causative genes for MR observed in one patient with ED.