Characterization of the nucleolar gene product, treacle, in Treacher Collins syndrome

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of cranio facial development caused by mutations in the gene TCOF1. Its gene product, treacle, consists mainly of a central repeat domain, which shows it to be structurally related to the nucleolar phosphoprotein Nopp140. Treacle remai ns mostly uncharacterized to date. Herein we show that it, like Nopp140, is a highly phosphorylated nucleolar protein. However, treacle fails to coloc alize with Nopp140 to Cajal (coiled) bodies. As in the case of Nopp140, cas ein kinase 2 appears to be responsible for the unusually high degree of pho sphorylation as evidenced by its coimmunoprecipitation with treacle. Based on these and other observations, treacle and Nopp140 exhibit distinct but o verlapping functions. The majority of TCOF1 mutations in TCS lead to premat ure termination codons that could affect the cellular levels of the full-le ngth treacle. We demonstrate however, that the cellular amount of treacle v aries less than twofold among a collection of primary fibroblasts and lymph oblasts and regardless of whether the cells were derived from TCS patients or healthy individuals. Therefore, cells of TCS patients possess a mechanis m to maintain wild-type levels of full-length treacle from a single allele.