Disease relevance of TCOF1

• One of these, Treacher Collins syndrome (TCOF1), is an autosomal dominant disorder of craniofacial development the features of which include conductive hearing loss and cleft palate [1].
• Mutations in the human TCOF1 gene have been identified in patients with Treacher Collins Syndrome (Mandibulofacial Dysostosis), an autosomal dominant condition affecting the craniofacial region [2].
• Since cardiac malformation and cryptorchidism have been associated with the TCOF1 syndrome, the proband was suspected to be a carrier of the mutated gene [3].
• Treacher Collins syndrome (TCOF1) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate [4].
• Treacher Collins syndrome with craniosynostosis, choanal atresia, and esophageal regurgitation caused by a novel nonsense mutation in TCOF1 [5].

High impact information on TCOF1

• Treacher Collins syndrome (TCS) is characterized by hypoplasia of the facial bones, cleft palate, and middle and external ear defects [6].
• Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities [6].
• Therefore, Tcof1/Treacle is a unique spatiotemporal regulator of ribosome biogenesis, a deficiency that disrupts neural crest cell formation and proliferation, causing the hypoplasia characteristic of TCS craniofacial anomalies [6].
• To investigate the developmental basis of TCS we generated a mouse model through germ-line mutation of Tcof1 [6].
• Thus, treacle haploinsufficiency in TCS patients might result in abnormal development caused by inadequate ribosomal RNA production in the prefusion neural folds during the early stages of embryogenesis [7].

Chemical compound and disease context of TCOF1

• Acute exposure to 400 mg/kg 13-cis retinoic acid (13-cis RA, isotretinoin, Accutane) on the ninth day postfertilization in mice (a time that corresponds to the fourth week postfertilization in humans) results in malformations that characterize mandibulofacial dysostosis (MFD, Treacher Collins syndrome) [8].
• The power and versatility of these computer-imaging techniques are demonstrated by examining living subjects with major craniofacial dysmorphology (Treacher-Collins syndrome and unilateral coronal synostosis); an anthropoid osteological specimen (Gorilla); and a fossil mammal skull [9].

Biological context of TCOF1

• The TCOF1 locus has been localized to chromosome 5q32-33 [4].
• 2. In the present study we have used the combined techniques of genetic linkage analysis and fluorescence in situ hybridization (FISH) to more accurately define the TCOF1 critical region [4].
• The highest maximum lod score was obtained between loci TCOF1 and D5S210 (Z = 10.52; theta = 0.02 +/- 0.07) [10].
• Based on this order, haplotype analysis suggests that the TCOF1 locus resides distal of CSF1R and proximal to SPARC within a region less than 1 Mb in size [10].
• TCOF1 encodes a low complexity protein of 1,411 amino acids, whose predicted protein structure reveals repeated motifs that mirror the organization of its exons [11].

Anatomical context of TCOF1

• Antisense-mediated down-regulation of treacle expression in Xenopus laevis oocytes reduced 2'-O-methylation of pre-rRNA [12].
• 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 [13].
• However, treacle fails to colocalize with Nopp140 to Cajal (coiled) bodies [14].
• 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 [14].
• Haploinsufficiency of Tcof1 leads to a deficiency in migrating neural crest cells, which results in severe craniofacial malformations [6].

Associations of TCOF1 with chemical compounds

• In the current investigation, a combination of cDNA library screening and rapid amplification of cDNA ends has permitted the isolation of the complete coding sequence of TCOF1, which is encoded by 26 exons and predicts a low complexity, serine/alanine-rich protein of approximately 144 kD [15].
• 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 [16].
• Later administration of retinoic acid prematurely and excessively kills ganglionic placodal cells and leads to a malformation complex virtually identical to the Treacher Collins syndrome [17].
• Ketamine for induction and intubation in Treacher-Collins syndrome [18].

Other interactions of TCOF1

• Exclusion of TCOF1 mutations in a case of bilateral Goldenhar syndrome and one familial case of microtia with meatal atresia [19].
• The finding of LisH motifs in both treacle and Nopp140 reinforces previous observations of functional similarities between these nucleolar proteins [20].
• 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 [21].
• The region has also been linked to at least four other genetic diseases, Treacher Collins syndrome, diastrophic dysplasia, limb-girdle muscular dystrophy, and an autosomal dominant deafness, by linkage analysis [22].
• The Treacher Collins syndrome locus was excluded from locus ADRB2R, which maps to 5q31----q32, and loci D5S22, D5S61, and D5S43, which map to 5q34----qter [23].

Analytical, diagnostic and therapeutic context of TCOF1

• Previous studies have localized the TCOF1 locus between D5S519 (proximal) and SPARC (distal), a region of 22 centirays as estimated by radiation hybrid mapping [24].
• We report the isolation of the entire mouse Tcof1 coding sequence (3960 bp) by performing a computer-based search for mouse cDNA clones homologous to TCOF1 and generating overlapping RT-PCR products from mouse RNA [2].
• Sequence analysis, identification of evolutionary conserved motifs and expression analysis of murine tcof1 provide further evidence for a potential function for the gene and its human homologue, TCOF1 [25].
• Real-time PCR analysis showed different melting temperatures of the amplified fragment containing normal allele and that harboring the 18 bp deletion, thus providing a rapid screening assay for this and other deletions of the TCOF1 gene [26].
• Site-directed mutagenesis has been used to recreate mutations observed in individuals with TCS [27].

References