Detection of an appropriate kinase activity in branchial arches I and II that coincides with peak expression of the Treacher Collins syndrome gene product, treacle. (1/83)

Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial disorder involving the mid and lower face and, in particular, the tissues affected arise solely from embryonic branchial arches I and II. TCOF1, the gene involved in TCS, has been cloned and although the function of the encoded protein, treacle, has not yet been established, it exhibits peak expression in the branchial arches. Treacle contains a series of repeating units of acidic and basic residues, which are predicted to contain putative casein kinase II (CKII) and protein kinase C (PKC) phosphorylation site motifs. In addition, treacle has weak homology to two phosphorylation-dependent nucleolar proteins, which shuttle between the cytoplasm and nucleolus. Based on these observations, phosphorylation of treacle may be important for its function. In this study, GST-treacle fusion peptides were constructed using particular TCOF1 exons that contained potential CKII and PKC phosphorylation sites. These were used as substrates in in vitro kinase assays and showed that treacle fusion peptides can be phosphorylated by the appropriate kinases. Furthermore, using tissue extracts we have demonstrated that in avian embryonic branchial arches I and II there is a kinase activity that can phosphorylate treacle peptides that is consistent with CKII site recognition. This activity coincides with the reported high expression of treacle in these tissues at early developmental stages and declines later in development.  (+info)

Increased levels of apoptosis in the prefusion neural folds underlie the craniofacial disorder, Treacher Collins syndrome. (2/83)

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of human craniofacial development that results from loss-of-function mutations in the gene TCOF1. Although this gene has been demonstrated to encode the nucleolar phosphoprotein treacle, the developmental mechanism underlying TCS remains elusive, particularly as expression studies have shown that the murine orthologue, Tcof1, is widely expressed. To investigate the molecular pathogenesis of TCS, we replaced exon 1 of Tcof1 with a neomycin-resistance cassette via homologous recombination in embryonic stem cells. Tcof1 heterozygous mice die perinatally as a result of severe craniofacial anomalies that include agenesis of the nasal passages, abnormal development of the maxilla, exencephaly and anophthalmia. These defects arise due to a massive increase in the levels of apoptosis in the prefusion neural folds, which are the site of the highest levels of Tcof1 expression. Our results demonstrate that TCS arises from haploinsufficiency of a protein that plays a crucial role in craniofacial development and indicate that correct dosage of treacle is essential for survival of cephalic neural crest cells.  (+info)

Characterization of the nucleolar gene product, treacle, in Treacher Collins syndrome. (3/83)

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial 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 remains mostly uncharacterized to date. Herein we show that it, like Nopp140, is a highly phosphorylated nucleolar protein. However, treacle fails to colocalize with Nopp140 to Cajal (coiled) bodies. As in the case of Nopp140, casein kinase 2 appears to be responsible for the unusually high degree of phosphorylation as evidenced by its coimmunoprecipitation with treacle. Based on these and other observations, treacle and Nopp140 exhibit distinct but overlapping functions. The majority of TCOF1 mutations in TCS lead to premature termination codons that could affect the cellular levels of the full-length treacle. We demonstrate however, that the cellular amount of treacle varies less than twofold among a collection of primary fibroblasts and lymphoblasts and regardless of whether the cells were derived from TCS patients or healthy individuals. Therefore, cells of TCS patients possess a mechanism to maintain wild-type levels of full-length treacle from a single allele.  (+info)

Correction of severe facial deformity. (4/83)

A craniofacial team has been developed to corrdinate the treatment of patients with severe facial deformity and to minimize the surgical risks. Two hundred patients have been evaluated in the last 4 years and more than 100 treated by this team to correct orbital hypertelorism, oxycephaly and plagiocephaly with exophthalmos, features of Crouzon's disease and Apert's and Treacher Collins syndromes, hemifacial microsomia, and severe lower facial deformity and malocclusion. Surgical principles include extensive subperiosteal stripping of bone, osteotomy as necessary, and repositioning maintained by bone grafts. Postoperative evaluation is being maintained for 5 years or to maturity in younger children. Although many of the results are less than perfect, there has been sufficient improvement, especially psychologic and functional, to warrant continuation of the surgical program under closely controlled conditions.  (+info)

Msx2 is a repressor of chondrogenic differentiation in migratory cranial neural crest cells. (5/83)

During early mouse embryogenesis, cranial neural crest cells (CNCC) emigrate from the posterior midbrain and rhombomeres 1 and 2 of the anterior hindbrain into the first branchial arch-derived maxillary and mandibular processes and there provide cell lineages for several phenotypes, including cartilage, bone, and tooth. Here, we report that Sox9 and Msx2 were coexpressed in a subpopulation of CNCC during their migration. Because Sox9 is a transactivator of chondrogenesis, and Msx genes can act as transcriptional repressors, we hypothesized that Sox9 expression indicates the determination of CNCC-derived chondrogenic cell lineage and that Msx2 represses chondrogenic differentiation until CNCC migration is completed within the mandibular processes. To test whether Msx2 represses chondrogenesis, we designed experiments to inhibit Msx2 function in migratory CNCC in primary cultures through the expression of loss-of-function Msx2 mutants. We showed that infection of migratory CNCC with adenovirus Msx2 mutants accelerated the rate and extent of chondrogenesis, as indicated by the expression level of type II collagen and aggrecan, and the amount of alcian blue staining. Adenovirus infections did not apparently interfere with CNCC proliferation or migration. These findings suggest that an important early event in craniofacial morphogenesis is a transient expression of both Sox9 and Msx2 during emigration into the forming mandibular processes followed by restricted expression of Sox9 within CNCC- derived chondroprogenitor cells. We conclude that Msx2 serves as a repressor of chondrogenic differentiation during CNCC migration.  (+info)

A new sequence motif linking lissencephaly, Treacher Collins and oral-facial-digital type 1 syndromes, microtubule dynamics and cell migration. (6/83)

A previously unidentified sequence motif has been identified in the products of genes mutated in Miller-Dieker lissencephaly, Treacher Collins, oral-facial-digital type 1 and contiguous syndrome ocular albinism with late onset sensorineural deafness syndromes. An additional homologous motif was detected in a gene product fused to the fibroblast growth factor receptor type 1 in patients with an atypical stem cell myeloproliferative disorder. In total, over 100 eukaryotic intracellular proteins are shown to possess a LIS1 homology (LisH) motif, including several katanin p60 subunits, muskelin, tonneau, LEUNIG, Nopp140, aimless and numerous WD repeat-containing beta-propeller proteins. It is suggested that LisH motifs contribute to the regulation of microtubule dynamics, either by mediating dimerization, or else by binding cytoplasmic dynein heavy chain or microtubules directly. The predicted secondary structure of LisH motifs, and their occurrence in homologues of Gbeta beta-propeller subunits, suggests that they are analogues of Ggamma subunits, and might associate with the periphery of beta-propeller domains. The finding of LisH motifs in both treacle and Nopp140 reinforces previous observations of functional similarities between these nucleolar proteins. Uncharacterized LisH motif-containing proteins represent candidates for other diseases associated with aberrant microtubule dynamics and defects of cell migration, nucleokinesis or chromosome segregation.  (+info)

Genetic mutations in certain head and neck conditions of interest to the dentist. (7/83)

This article identifies certain syndromes of the head and neck, which a dentist may see in clinical practice, and relates these syndromes to their sites of mutation on involved genes. This paper is timely with the near completion of the Human Genome Project, the mapping of the entire human genetic material. Knowing the site of the genetic lesion is important in helping clinicians understand the genetic basis for these conditions, and may help in our future understanding of remedies and treatments.  (+info)

Novel autosomal dominant mandibulofacial dysostosis with ptosis: clinical description and exclusion of TCOF1. (8/83)

BACKGROUND: Treacher Collins syndrome (TCS), the most common type of mandibulofacial dysostosis (MFD), is genetically homogeneous. Other types of MFD are less common and, of these, only the Bauru type of MFD has an autosomal dominant (AD) mode of inheritance established. Here we report clinical features of a kindred with a unique AD MFD with the exclusion of linkage to the TCS locus (TCOF1) on chromosome 5q31-q32. METHODS: Six affected family members underwent a complete medical genetics physical examination and two affected subjects had skeletal survey. All available medical records were reviewed. Linkage analysis using the markers spanning the TCOF1 locus was performed. One typically affected family member had a high resolution karyotype. RESULTS: Affected subjects had significant craniofacial abnormalities without any significant acral changes and thus had a phenotype consistent with a MFD variant. Distinctive features included hypoplasia of the zygomatic complex, micrognathia with malocclusion, auricular abnormalities with conductive hearing loss, and ptosis. Significantly negative two point lod scores were obtained for markers spanning the TCOF1 locus, excluding the possibility that the disease in our kindred is allelic with TCS. High resolution karyotype was normal. CONCLUSIONS: We report a kindred with a novel type of MFD that is not linked to the TCOF1 locus and is also clinically distinct from other types of AD MFD. Identification of additional families will facilitate identification of the gene causing this type of AD MFD and further characterisation of the clinical phenotype.  (+info)

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