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PubMed1996

Treacher Collins syndrome.

Treacher Collins syndrome is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. In the absence of a candidate gene, a positional cloning approach has been used to isolate the mutated gene which maps to chromosome 5q31.3-32. Flanking markers were identified and a yeast artificial chromosome and cosmid contig of the region defined by these markers was created as a prelude to the creation of a transcript map of the region. Analysis of genes isolated using this approach resulted in the identification of the mutated gene. While the function of the gene remains unknown, the identification of 20 mutations spread throughout the gene, all of which would result in the insertion of a premature termination codon into the reading frame, suggests that the mechanism underlying the disease is haploinsufficiency.

Animals↗
PubMed1998

Mutations in the Treacher Collins syndrome gene lead to mislocalization of the nucleolar protein treacle.

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. The TCS gene ( TCOF1 ), which is localized to chromosome 5q32-q33.1, recently has been identified by positional cloning. Analysis of TCOF1 revealed that the majority of TCS mutations result in the creation of a premature termination codon. The function of the predicted protein, treacle, is unknown, although indirect evidence from database analyses suggests that it may function as a shuttling nucleolar phosphoprotein. In the current study, we provide the first direct evidence that treacle is a nucleolar protein. An antibody generated against treacle shows that it localizes to the nucleolus. Fusion proteins tagged to a green fluorescent protein reporter were shown to localize to different compartments of the cell when putative nuclear localization signals were deleted. Parallel experiments using conserved regions of the murine homologue of TCOF1 confirmed these results. Site-directed mutagenesis has been used to recreate mutations observed in individuals with TCS. The resulting truncated proteins are mislocalized within the cell, which further supports the hypothesis that an integral part of treacle's function involves shuttling between the nucleolus and the cytoplasm. TCS is, therefore, the first Mendelian disorder resulting from mutations which lead to aberrant expression of a nucleolar protein.

Animals↗
PubMed1998

The Treacher Collins syndrome (TCOF1) gene product, treacle, is targeted to the nucleolus by signals in its C-terminus.

The TCOF1 gene product, treacle, responsible for the craniofacial disorder Treacher Collins syndrome, has been predicted to be a member of a class of nucleolar phosphoproteins based on its primary amino acid sequence. Treacle is a low complexity protein with ten repeating units of acidic and basic residues, each of which contains a large number of putative casein kinase 2 and protein kinase C phosphorylation sites. In addition, the C-terminus of treacle contains multiple putative nuclear localization signals. The overall structure of treacle, as well as sequence similarity to several nucleolar phosphoproteins, predicts that treacle is a member of this class of proteins. Using green fluorescent protein fusion constructs with the full-length and deleted domains of the murine homolog of treacle, we demonstrate that the cellular localization of treacle is nucleolar. This localization is mediated by the last 41 residues of the C-terminus (residues 1262-1302). At least two functional nuclear localization signals have been identified in the protein, one between residues 1176 and 1270 and the second within the last 32 residues of the protein (1271-1302). The nucleolar localization signal is disrupted by two constructs that split the C-terminal region between residues 1270 and 1271. This study provides the first direct analysis of treacle and demonstrates that the protein involved in TCOF1 is a nucleolar protein.

Amino Acid Sequence↗
PubMed1999

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.

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.

Animals↗
PubMed2000

Increased levels of apoptosis in the prefusion neural folds underlie the craniofacial disorder, Treacher Collins syndrome.

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.

Animals↗
PubMed2005

The Treacher Collins syndrome (TCOF1) gene product is involved in pre-rRNA methylation.

Treacher Collins syndrome (TCS) is characterized by defects in craniofacial development, which results from mutations in the TCOF1 gene. TCOF1 encodes the nucleolar phosphoprotein treacle, which interacts with upstream binding factor (UBF) and affects transcription of the ribosomal DNA gene. The present study shows participation of treacle in the 2'-O-methylation of pre-rRNA. Antisense-mediated down-regulation of treacle expression in Xenopus laevis oocytes reduced 2'-O-methylation of pre-rRNA. Analysis of RNA isolated from wild-type and Tcof1+/- heterozygous mice embryos from strains that exhibit a lethal phenotype showed significant reduction in 2'-O-methylation at nucleotide C463 of 18S rRNA. The level of pseudouridylation of U1642 of 18S rRNA from the same RNA samples was not affected suggesting specificity. There is no significant difference in rRNA methylation between wild-type and heterozygous embryos of DBA x BALB/c mice, which have no obvious craniofacial phenotype. The function of treacle in pre-rRNA methylation is most likely mediated by its direct physical interaction with NOP56, a component of the ribonucleoprotein methylation complex. Although treacle co-localizes with UBF throughout mitosis, it co-localizes with NOP56 and fibrillarin, a putative methyl transferase, only during telophase when rDNA gene transcription and pre-rRNA methylation are known to commence. These observations suggest that treacle might link RNA polymerase I-catalyzed transcription and post-transcriptional modification of pre-rRNA. We hypothesize that haploinsufficiency of treacle in TCS patients results in inhibition of production of properly modified mature rRNA in addition to inhibition of rDNA gene transcription, which consequently affects proliferation and proper differentiation of specific embryonic cells during development.

Animals↗
PubMed2002

Mutation testing in Treacher Collins Syndrome.

OBJECTIVE: To report on a study where 97 subjects were screened for mutations in the Treacher Collins syndrome (TCS) gene TCOF1. METHOD: Ninety-seven subjects with a clinical diagnosis of TCS were screened for potential mutations in TCOF1, by means of single strand conformation polymorphism (SSCP) analysis. In those subjects where potential mutations were detected, sequence analysis was performed to determine the site and type of mutation present. RESULTS: Thirty-six TCS-specific mutations are reported including 27 deletions, six point mutations, two splice junction mutations, and one insertion/deletion. This brings the total number of mutations reported to date to 105. CONCLUSION: The importance of detection of these mutations is mainly in postnatal diagnosis and genetic counselling. Knowledge of the family specific mutation may also be used in prenatal diagnosis to confirm whether the foetus is affected or not, and give the parents the choice of whether to continue with the pregnancy.

DNA Mutational Analysis↗
PubMed1996

Diagnostic difficulties in cases of sudden death in infants with mandibular hypoplasia.

Infants with mandibular hypoplasia are at risk of sudden death from cardiorespiratory arrest secondary to upper airway obstruction. To evaluate diagnostic difficulties that may occur at autopsy in such infants, the autopsy files at the Adelaide Children's Hospital (ACH) for 36 years, 1959 to 1994, were reviewed. Eight cases were identified (age range, 2 days to 10 months; mean age, 2.2 months; male/female ratio, 5:3). In all cases, death was considered most likely due to airway obstruction related to mandibular hypoplasia or its treatment. Although death occurred in the hospital in five cases, one infant suddenly collapsed at home while feeding and died, and two infants were unexpectedly found dead in their cribs at home. Three infants had defined genetic syndromes. Although all the infants had histories of antemortem airway obstruction, one infant had normal oxygen saturation studies before hospital discharge, and one infant had a tracheostomy. Acute bronchopneumonia was an exacerbating factor in one case. Assessment of mandibular size is important in any infant who dies unexpectedly; and if hypoplasia is found, careful review of the clinical details for evidence of airway obstruction is necessary to help distinguish these cases from sudden infant death syndrome (SIDS). Sudden death may, however, occur in infants with mandibular hypoplasia in spite of apparent clinical stability before death with no significant recent episodes of oxygen desaturation.

Airway Obstruction↗
PubMed1980

The absent lateral canthal tendon: reconstruction using a Y graft of palmaris longus tendon.

Absence of the lateral canthal tendon, whether congenital or acquired, imposes cosmetic and functional deformities that are surgically correctable. We propose a means of reconstructing the lateral canthal tendon using a Y graft of palmaris longus tendon. The benefits of this method are discussed. We believe it offers an alternative approach for supporting the lateral canthus and lower eyelid, and is especially useful when reestablishment of the lateral canthal tendon is necessary because of local tissue destruction or congenital absence. Three patients with congenital absence of the lateral canthal tendon are presented.

Abnormalities, Multiple↗
PubMed1989

Detailed morphometry of the nose in patients with Treacher Collins syndrome.

Patients with Treacher Collins syndrome were studied regarding 10 nasal, 1 orbital, and 4 facial measurements as well as 10 facial proportion indexes. Data from 15 to 24 patients were related to normal values. The most normal feature was found to be the nose, whose basic measurements were optimal. Because harmony between the nose and the face is a basic requirement of aesthetic balance in a healthy face, the nose in these patients is the key for calculating changes in the markedly damaged general framework of the face. Abnormal proportion indexes must be corrected by adjusting the abnormal measurement to its optimal level. Thus, the abnormally short bizygomatic width had to be increased by a mean of 13 to 21 mm. Both the nose and the face were usually normal-long, producing acceptable proportions in these patients. Some size disproportions were found between the root and the soft nose. Their adjustment should be part of the general plan to correct the face of a patient with Treacher Collins syndrome.

Adolescent↗
PubMed1994

Mandibular lengthening by distraction for airway obstruction in Treacher-Collins syndrome.

Mandibular lengthening by distraction was performed in a 6-year-old tracheostomy-dependent Treacher-Collins syndrome patient. Detailed preoperative imaging revealed an occluded retrotongue base pharyngeal airway, which, following mandibular distraction, became patent and permitted tracheostomy removal. Mandibular distraction as a technique must be targeted toward clinical problems--management of upper-airway obstruction may be one such scenario.

Airway Obstruction↗
PubMed1994

Inherited Treacher-Collins syndrome in twins after artificial insemination.

We present two cases of the Treacher-Collins syndrome and one case of plagiocephalus in a trigeminus childbirth resulting from artificial insemination. The mother, although affected with the Treacher-Collins syndrome, was not diagnosed before the birth of her children. Genetic counseling did not occur. Medical and forensic problems resulting from modern techniques of reproduction are briefly discussed.

Adult↗