Alternative titles; symbols
HGNC Approved Gene Symbol: TCOF1
SNOMEDCT: 82203000; ICD10CM: Q75.4;
Cytogenetic location: 5q32-q33.1 Genomic coordinates (GRCh38) : 5:150,357,697-150,400,293 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q32-q33.1 | Treacher Collins syndrome 1 | 154500 | Autosomal dominant | 3 |
By positional cloning, the Treacher Collins Syndrome Collaborative Group (1996) identified a novel gene of unknown function, which they designated treacle, within the Treacher Collins syndrome (TCS; 154500) critical region at chromosome 5q. Northern blot analysis indicated that the gene is expressed in a variety of fetal and adult tissues. Dixon et al. (1997) isolated the coding sequence of the gene, designated TCOF1, and determined that it encodes a low complexity, serine/alanine-rich protein of approximately 144 kD. The deduced 1,411-amino acid protein has 3 domains with unique N and C termini and a large central repeat domain. Wise et al. (1997) showed that the repeat protein motifs are shared with nucleolar trafficking proteins in other species and are predicted to be highly phosphorylated by casein kinase II (115440). Consistent with this, the full-length TCOF1 protein sequence also contains putative nuclear and nucleolar localization signals.
So et al. (2004) identified 1 major and 2 minor in-frame splice variants of treacle that differed from the transcript reported by the Treacher Collins Syndrome Collaborative Group (1996). The major variant includes an additional 231-nucleotide exon, 6A, which introduces an additional repeat of alternating basic and acidic regions and a novel functional monopartite nuclear localization signal (KRAKK). The deduced protein contains 1,488 amino acids and has a calculated molecular mass of 152 kD. Northern blot analysis of HeLa cells detected this variant at about 5.5 kb. RT-PCR detected 1.5- to 3.7-fold higher expression of variants containing exon 6A than those lacking this exon in all human tissues and cell lines examined. The 2 minor variants identified by So et al. (2004) include one containing a different additional exon (16A) and the other lacking exon 19.
Dixon et al. (1997) isolated the murine homolog of the TCOF1 gene and showed that it encodes a protein of 133 kD. Interspecies comparison indicated that the proteins display 61.5% identity, with the level of conservation being greatest in the regions of acidic/basic amino acid repeats and nuclear localization signals. These features are shared with the nucleolar phosphoproteins. Confirmation that the gene isolated was orthologous with the Treacher Collins syndrome gene was provided by the demonstration that it mapped to central mouse chromosome 18 in a region of conserved synteny with 5q21-q33. The gene was found to be expressed in a wide variety of embryonic and adult tissues of the mouse. So et al. (2004) examined mouse Tcof1 transcripts and identified a variant containing an additional exon (16A).
Gladwin et al. (1996) defined the intron-exon structure of the TCOF1 gene, identified 7 exons, and derived intronic sequences. Wise et al. (1997) reported the complete exon/intron genomic structure of the TCOF1 gene and its complete coding sequence. The TCOF1 gene contains 26 exons.
So et al. (2004) identified 2 additional exons within the TCOF1 gene: exon 6A and exon 16A. The sequence containing exon 6A transcribes the major TCOF1 isoform.
The Treacher Collins Syndrome Collaborative Group (1996) found that the treacle gene (TCOF1), which is mutant in Treacher Collins syndrome, is located on chromosome 5q in a gene-rich region of the human genome. DTDST (606718), CSF1R, PDGFRB (173410), and CDX1 (600746) are within approximately 900 kb proximal of the TCOF1 locus, determined by a combination of radiation hybrid and YAC/cosmid contig analysis. The same process demonstrated that DHLAG, RPS14, HSST (600853), GPX3 (138321), and ANX6 are distal to TCOF1. Moreover, a large number of additional genes of unknown function had been mapped to the region.
The Treacher Collins Syndrome Collaborative Group (1996) stated that the clinical phenotype of Treacher Collins syndrome suggests that the responsible gene plays a fundamental role in early embryonic development, particularly in development of the craniofacial complex. Dixon et al. (1997) observed that peak levels of expression in the developing mouse embryo were present at the edges of the neural folds immediately before fusion, and also in the developing branchial arches at the time of critical morphogenetic events. Dixon et al. (1997) commented that these observations support a role for the gene in the development of the craniofacial complex and provide further evidence that the gene encodes a protein that may be involved in nucleolar-cytoplasmic transport.
Jones et al. (1999) used treacle fusion peptides to demonstrate that the region encoded by exon 9 is phosphorylated in vitro by both casein kinase II and protein kinase C (see 176960). Furthermore, they found such a kinase activity to be present in protein extracts from several embryonic avian tissues, including branchial arches I and II.
Using database mining and protein structural prediction programs, Emes and Ponting (2001) identified a sequence motif in the products of genes mutated in Miller-Dieker lissencephaly (LIS1; 601545), Treacher Collins, oral-facial-digital type 1 (CXORF5; 300170), and ocular albinism with late-onset sensorineural deafness (TBL1X; 300196) syndromes. Over 100 eukaryotic intracellular proteins were found to possess a LIS1 homology motif, including several katanin p60 (606696) subunits, muskelin (605623), Nopp140 (NOLC1; 602394), the plant proteins tonneau and LEUNIG, slime mold protein aimless, and numerous WD repeat-containing beta-propeller proteins. The authors suggested that LIS1 homology motifs may contribute to the regulation of microtubule dynamics, either by mediating dimerization, or else by binding cytoplasmic dynein heavy chain (600112) or microtubules directly. The predicted secondary structure of LIS1 homology motifs, and their occurrence in homologs of G-beta beta-propeller subunits, suggests that they are analogs of G-gamma subunits, and might associate with the periphery of beta-propeller domains. The finding of LIS1 homology motifs in both treacle and Nopp140 reinforces previous observations of functional similarities between these nucleolar proteins.
Valdez et al. (2004) showed that treacle is involved in ribosomal DNA gene transcription by interacting with upstream binding factor (UBF; 600673). Immunofluorescence labeling showed that treacle and UBF colocalize to specific nucleolar organizer regions and cosegregate within nucleolar caps of actinomycin D-treated HeLa cells; biochemical analysis showed the association of treacle and UBF with chromatin. Immunoprecipitation and the yeast 2-hybrid system both suggested physical interaction of the 2 nucleolar phosphoproteins. Downregulation of treacle expression using specific short interfering RNA (siRNA) resulted in inhibition of ribosomal DNA transcription and cell growth. A similar correlation was observed in Tcof1 +/- mouse embryos that exhibited craniofacial defects and growth retardation. Valdez et al. (2004) concluded that treacle haploinsufficiency in patients with Treacher Collins syndrome may result in abnormal development caused by inadequate ribosomal RNA production in the prefusion neural folds during the early stages of embryogenesis.
Gonzales et al. (2005) showed that antisense-mediated downregulation of Tcof1 expression in Xenopus oocytes reduced 2-prime-O-methylation of pre-rRNA. Analysis of RNA isolated from wildtype and Tcof1 +/- mice embryos from strains that exhibit a lethal phenotype showed significant reduction in 2-prime-O-methylation at nucleotide 463C of 18S rRNA. There was no significant difference in rRNA methylation between wildtype and heterozygous embryos of DBAxBALB/c mice, which have no obvious craniofacial phenotype. The authors proposed that the function of TCOF1 in pre-rRNA methylation is most likely mediated by its direct physical interaction with NOP56 (614154), a component of the ribonucleoprotein methylation complex. Although TCOF1 colocalizes with UBF throughout mitosis, it colocalizes with NOP56 and fibrillarin (FBL; 134795), a putative methyltransferase, only during telophase when rDNA gene transcription and pre-rRNA methylation are known to commence. The authors suggested that TCOF1 might link RNA polymerase I-catalyzed transcription and posttranscriptional modification of pre-rRNA. Gonzales et al. (2005) hypothesized that haploinsufficiency of TCOF1 in TCS patients may result 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.
KBTBD8 (616607) functions as an adaptor for substrate recognition by the ubiquitin ligase CUL3 (603136). Using mass spectrometric analysis, Werner et al. (2015) found that KBTBD8 interacted with TCOF1 and NOLC1. CUL3-KBTBD8 monoubiquitinated TCOF1 and NOLC1 in a manner that required the cofactor beta-arrestin (see 107940). Knockdown of KBTBD8, TCOF1, or NOLC1 in human embryonic stem cells (hESCs) via short hairpin RNA inhibited hESC differentiation into neural crest cells and accelerated hESC differentiation into central nervous system (CNS) precursors. Affinity purification revealed that ubiquitinated TCOF1-NOLC1 complexes engaged RNA polymerase I into complexes with the small ribosomal processing complex. Werner et al. (2015) hypothesized that KBTBD8-dependent ubiquitination drives formation of a TCOF1-NOLC1 platform in hESCs that connects RNA polymerase I with ribosome modification enzymes at specific mRNAs to delay accumulation of CNS precursor proteins until neural crest specification has occurred.
The Treacher Collins Syndrome Collaborative Group (1996) identified different mutations in the TCOF1 gene in each of 5 unrelated families with Treacher Collins syndrome. All of the mutations were predicted to result in premature termination of the gene product.
Gladwin et al. (1996) used oligonucleotide primers designed from the intronic sequence to amplify each exon from genomic DNA. They amplified exons from the DNA of one affected individual from each of 33 Treacher Collins families and screened for mutations using SSCP. They identified mobility shifts in 4 exons. The mutations identified by Gladwin et al. (1996) included 3 deletions (of either 1 or 2 nucleotides), an insertion of a single nucleotide, and an unusual splicing mutation. They reported that these 5 mutations are all different from the 5 mutations previously reported by the Treacher Collins Syndrome Collaborative Group (1996) and that all 10 of the mutations found in TCOF1 are nonsense or frameshift mutations that would be predicted to result in premature termination of the protein product. None of the TCOF1 mutations found in affected individuals were detected on chromosomes from 200 controls. Gladwin et al. (1996) noted that all reported mutations were unique to each family.
Dixon (1996) reviewed the clinical and molecular features of Treacher Collins syndrome. A total of 20 mutations in the TCOF1 gene had been identified, of which 2 were nonsense mutations, 5 were insertions, 11 were deletions, and 2 were splicing mutations. A 5-bp deletion had been observed in 4 unrelated families. All of the mutations observed resulted in introduction of premature termination codons into the reading frame, suggesting haploinsufficiency as the molecular mechanism underlying the disorder.
Edwards et al. (1997) reported several previously undescribed mutations throughout the TCOF1 gene in patients with Treacher Collins syndrome, bringing the total number of reported mutations to 35, which represented a detection rate of 60%. All but one of the mutations resulted in the introduction of a premature termination codon into the predicted protein. Moreover, the mutations were largely family specific, although a common 5-bp deletion in exon 24 was seen in 7 different families and a recurrent splicing mutation in intron 3 in 2 different families. The mutational spectrum supported the hypothesis that TCS results from haploinsufficiency. Throughout the open reading frame, Wise et al. (1997) detected 8 mutations in TCS families and several polymorphisms (e.g., 154500.0003).
Splendore et al. (2000) screened 28 families with a clinical diagnosis of Treacher Collins syndrome for mutations in the 25 coding exons of the TCOF1 gene and their adjacent splice junctions, using SSCP and direct sequencing. Pathogenic mutations were detected in 26 patients (93%), bringing the number of known disease-causing mutations from 35 to 51. A clustering of pathogenic mutations was identified. They confirmed a previous finding that TCOF1 has an unusually high rate of single-nucleotide polymorphisms (SNPs) within its coding region.
In 33 of 60 patients (55%) with Treacher Collins syndrome, Splendore et al. (2002) identified 31 mutations in the TCOF1 gene, 27 of which were novel. Five exons accounted for over 50% of the mutations, with exons 23 and 24 being the main hotspots. All mutations except 1, a tyr50-to-cys substitution (Y50C; 606847.0005), resulted in a truncated protein.
In a patient with the clinical diagnosis of Treacher Collins syndrome, Shoo et al. (2004) identified a heterozygous 2-bp deletion in the TCOF1 gene (606847.0006). The mother was clinically unaffected but the same mutation was found in her leukocytes, hair root bulbs, buccal mucosa, urine, and stool. Maternal grandparents did not have the mutation. Because the mother had the mutation in cells derived from all 3 germ layers, Shoo et al. (2004) at first suspected that the mutation was nonpenetrant; however, they could not detect the mutation in her skin fibroblasts, suggesting that she was mosaic.
Shows et al. (2006) reported on an infant rhesus macaque (Macaca mulatta) that displayed the Treacher Collins syndrome phenotype and was identified at the California National Primate Research Center. They cloned the TCOF1 coding region from a normal rhesus macaque and sequenced it. The rhesus homolog of TCOF1 was found to be 91.6% identical in cDNA sequence and 93.8% identical in translated protein sequence to human TCOF1. Sequencing of TCOF1 in the TCS-affected rhesus macaque showed no mutations within the coding region or splice sites; however, real-time quantitative PCR showed an 87% reduction of spleen TCOF1 mRNA in the affected macaque when compared with normal macaque spleen. The presumed haploinsufficiency of functional protein, especially at the critical timepoint in development when TCOF1 is normally expressed in large quantities to promote development of the craniofacial skeleton, may account for the phenotype; the lower level of mRNA was not caused by nonsense-mediated mRNA decay because a nonsense mutation was not found in the coding region. A promoter mutation could not be excluded.
Bowman et al. (2012) identified pathogenic sequence variants in the TCOF1 gene in 92 (50.5%) of 182 unrelated patients with a clinical diagnosis consistent with Treacher Collins syndrome. Of those with a sequence change, 57% had a frameshift or mutation disrupting the start codon, 23% had a nonsense mutation, 16% had a splice site mutation, and 4% had a missense mutation. In addition, 5.2% of patients had an intragenic deletion of the TCOF1 gene. Thus, the majority of TCOF1 mutations lead to a loss of protein function and haploinsufficiency.
Associations Pending Confirmation
For a discussion of a possible association between craniofacial microsomia and variation in the TCOF1 gene, see 164210.
Exclusion Studies
Splendore et al. (2002) found no mutations in the TCOF1 gene in 3 disorders with features overlapping those of Treacher Collins syndrome: Goldenhar syndrome (164210), Nager syndrome (154400), and Miller syndrome (263750).
Haworth et al. (2001) isolated the dog homolog of the TCOF1 gene from a dog embryonic head/neck cDNA library. The protein shows a similar 3-domain structure to that described for human TCOF1, but the dog gene lacks exon 10 and contains 2 exons not present in the human sequence. In addition, exon 19 is differentially spliced in the dog. They mapped the dog TCOF1 gene to chromosome 4q31, a region showing syntenic homology with human chromosome 5. Genetic analysis of DNA of dogs from 13 different breeds identified 9 DNA sequence variants, 3 of which gave rise to amino acid substitutions. Grouping dogs according to head type showed that a 396C-T variant, leading to a pro117-to-ser amino acid substitution, is associated with skull/face shape in this dog panel. The numbers were small, but the association between the T allele and brachycephaly, broad skull/short face, was highly significant (P = 0.000024). The short period of time during which the domestic dog breeds have been established suggests that this mutation has arisen only once in the history of dog domestication.
Dixon et al. (2006) created Tcof1 +/- mouse lines and noted that the extent and severity of the phenotype was dependent upon the genetic background. Tcof1 +/- neonates obtained through an intercross of DBA Tcof1 heterozygotes and wildtype C57BL/6 mice exhibited a phenotype that mimicked TCS. The heads of Tcof1 +/- neonates were small and dome shaped, with anteroposterior shortening and severe frontonasal dysplasia. Tcof1 +/- neonates displayed gasping behavior and abdominal distention and died within 24 hour of birth. Skeletal analysis indicated that Tcof1 +/- neonates died from respiratory arrest due to malformations of the nasal, premaxilla, maxilla, and palatine skeletal elements. Whole-embryo culture of wildtype and Tcof1 +/- mouse embryos showed that Tcof1 haploinsufficiency resulted in neural crest cell hypoplasia due to neuroepithelial-specific apoptosis. Furthermore, Dixon et al. (2006) found that Tcof1 haploinsufficiency resulted in deficient production of mature ribosomes, leading to apoptosis and reduced cell proliferation.
Richter et al. (2010) used Tcof1 mutant mice to dissect the developmental mechanisms underlying congenital hearing loss. Effective cavitation of the middle ear was intimately linked to growth of the auditory bulla, the neural crest cell-derived structure that encapsulates all middle ear components, and defects in these processes had a profoundly detrimental effect on hearing.
The designation 'treacle' may be best used for the protein encoded by the TCOF1 locus. The word treacle clearly comes from Treacher Collins and may have been devised by the British members of the collaborative group where 'treacle' is the equivalent of the American's 'molasses.'
In affected members of a family with Treacher Collins syndrome (TCS1; 154500), the Treacher Collins Syndrome Collaborative Group (1996) found a C-to-T transition at nucleotide 703 that created a stop codon in place of a glutamine residue, resulting in premature termination of the protein. The mutation created a BfaI site allowing the confirmation that this mutation was present in all of the affected but none of the unaffected family members.
Edwards et al. (1997) stated that this gln-to-ter mutation occurred at position 252 (Q252X).
Wise et al. (1997) described a patient with familial Treacher Collins syndrome (TCS1; 154500) who had an insertion of a single adenine after nucleotide 422 in exon 5 (422insA). The insertion caused a change from histidine to glutamine at codon 141 and a change in the subsequent amino acids, with a stop codon 33 amino acids beyond the site of the insertion.
In a patient with Treacher Collins syndrome (TCS1; 154500), Wise et al. (1997) demonstrated a mutation in the TCOF1 gene that consisted of deletion of 4 bp, ATAC, after nucleotide 497 (497delATAC). The deletion caused a change in codon 166 from asparagine to isoleucine and a change in the downstream amino acids until the point of a stop codon 44 amino acids beyond the deletion.
In a review of mutations in the TCOF1 gene causing Treacher Collins syndrome (TCS1; 154500), Splendore et al. (2000) found that the most frequent recurring mutation was a 5-bp deletion in exon 24 (4135-4139delGAAAA). This mutation was reported in 7 families by Edwards et al. (1997), was found by Splendore et al. (2000) in 6 unrelated patients, and was said to be responsible for approximately 16% of all reported cases.
In a patient with sporadic Treacher Collins syndrome (TCS1; 154500), Splendore et al. (2002) identified a 149A-G transition in exon 2 of the TCOF1 gene, resulting in a tyr50-to-cys (Y50C) substitution. Analysis of parental DNA indicated that the mutation arose de novo. The mutation was not detected in 100 control chromosomes. Splendore et al. (2002) noted that missense mutations causing Treacher Collins syndrome are rare (most are truncating mutations), and pointed out that human exons 1 and 2 are highly conserved, suggesting that the N terminus of the protein is an important functional domain.
In a patient with the clinical diagnosis of Treacher Collins syndrome (TCS1; 154500), Shoo et al. (2004) identified a heterozygous 2-bp deletion, 1408delAG, in the TCOF1 gene. The mother was clinically unaffected but the same mutation was found in her leukocytes, hair root bulbs, buccal mucosa, urine, and stool. Maternal grandparents did not have the mutation. Because the mother had the mutation in cells derived from all 3 germ layers, Shoo et al. (2004) at first suspected that the mutation was nonpenetrant; however, they could not detect the mutation in her skin fibroblasts, suggesting that she was mosaic.
In a 5-year-old girl with Treacher Collins syndrome (TCS1; 154500) and craniosynostosis, choanal atresia, and esophageal regurgitation, Horiuchi et al. (2004) identified a de novo 2731C-T transition in exon 17 of the TCOF1 gene, resulting in an arg911-to-ter (R911X) change that truncates the protein.
In a patient with typical Treacher Collins syndrome (TCS1; 154500), Marszalek et al. (2003) identified a heterozygous 18-bp deletion beginning at nucleotide 376 within the 5-prime splice site in exon 4 of the TCOF1 gene. The deletion included 3 bp of exon 4 and 15 bp of intron 4 and resulted in premature termination of the protein. Real-time PCR analysis showed different melting temperatures of the amplified fragments containing the normal allele and the mutated allele, which could be used as a rapid screening assay. Marszalek et al. (2003) stated that the deletion was the third largest found to date in the TCOF1 gene.
In a patient with Treacher Collins syndrome (TCS1; 154500), Splendore et al. (2002) identified a 1-bp deletion (4134delA) in exon 24 of the TCOF1 gene.
In a patient with Treacher Collins syndrome who had novel craniofacial and extracraniofacial features, Li et al. (2009) identified the same frameshift mutation (4365delA) in the TCOF1 sequence that includes an additional 231-nucleotide exon (6A). The mutation resulted in a read-through of the native stop codon of the TCOF1 gene, adding more than 80 novel amino acids to the 3-prime end of the protein. The authors noted that the patient also had a 1535T-C transition in TCOF1, resulting in a met512-to-thr substitution; this substitution was also present in his unaffected mother. Unusual features in the patient included encephalocele, marked malformation of the eyes, abnormal inner ear structures, and several anomalies that involved the thyroid, the thymus, the heart, an accessory spleen, ectopic adrenal gland tissue, and underdeveloped external genitalia.
In a female patient with sporadic Treacher Collins syndrome (TCS1; 154500), Splendore et al. (2000) identified a 4-bp deletion (1406_1409delAGAG) in exon 10 of the TCOF1 gene.
In 2 Hutterite sisters with Treacher Collins syndrome, originally reported by Lowry et al. (1985) and thought to have an autosomal recessive form of the disorder, Caluseriu et al. (2013) identified heterozygosity for the same 4-bp deletion in the TCOF1 gene. The deletion creates a frameshift starting at codon lys470, and the new reading frame ends in a stop codon 21 positions downstream. The deletion was also present in the girls' father, supporting incomplete penetrance of the disorder.
In a female with Treacher Collins syndrome (TCS1; 154500), Caluseriu et al. (2013) identified a de novo heterozygous 1-bp duplication (c.2876dup) in exon 19 of the TCOF1 gene, resulting in a frameshift and a stop codon 5 positions downstream. The mutation was predicted to result in an mRNA product that might be targeted for nonsense-mediated decay, or if translation should proceed, for a prematurely terminated protein.
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Marszalek, B., Wisniewski, S. A., Wojcicki, P., Kobus, K., Trzeciak, W. H. Novel mutation in the 5-prime splice site of exon 4 of the TCOF1 gene in the patient with Treacher Collins syndrome. Am. J. Med. Genet. 123A: 169-171, 2003. [PubMed: 14598341] [Full Text: https://doi.org/10.1002/ajmg.a.20312]
Richter, C. A., Amin, S., Linden, J., Dixon, J., Dixon, M. J., Tucker, A. S. Defects in middle ear cavitation cause conductive hearing loss in the Tcof1 mutant mouse. Hum. Molec. Genet. 19: 1551-1560, 2010. [PubMed: 20106873] [Full Text: https://doi.org/10.1093/hmg/ddq028]
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Shows, K. H., Ward, C., Summers, L., Li, L., Ziegler, G. R., Hendrickx, A. G., Shiang, R. Reduced TCOF1 mRNA level in a rhesus macaque with Treacher Collins-like syndrome: further evidence for haploinsufficiency of treacle as the cause of disease. Mammalian Genome 17: 168-177, 2006. [PubMed: 16465596] [Full Text: https://doi.org/10.1007/s00335-005-0079-y]
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