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Identification of three novel TCOF1 mutations in patients with Treacher Collins Syndrome.

ABSTRACT: Here we describe three novel TCOF1 mutations found in unrelated patients with Treacher Collins syndrome. These mutations include one deletion, NM_001135243.2:c.2604_2605delAG (p.Gly869Glufs*3), and two substitutions, NM_001135243.2:c.2575C>T (p.Gln859*) and NM_001135243.2:c.4111G>T (p.Glu1371*). These mutations cause shortening of a protein called Treacle in patients with features typical of TCS. Continuous identification of new mutations is important to expand the mutation base, which is helpful in the diagnosis of both patients and their families.

SUBMITTER: Marszalek-Kruk BA

PROVIDER: S-EPMC8476508 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Identification of three novel TCOF1 mutations in patients with Treacher Collins Syndrome.

Marszałek-Kruk Bożena Anna BA Wójcicki Piotr P

Human genome variation 20210927 1

Here we describe three novel TCOF1 mutations found in unrelated patients with Treacher Collins syndrome. These mutations include one deletion, NM_001135243.2:c.2604_2605delAG (p.Gly869Glufs*3), and two substitutions, NM_001135243.2:c.2575C>T (p.Gln859*) and NM_001135243.2:c.4111G>T (p.Glu1371*). These mutations cause shortening of a protein called Treacle in patients with features typical of TCS. Continuous identification of new mutations is important to expand the mutation base, which is helpfu ...[more]

PMID: 34580285

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Novel mutations of TCOF1 gene in European patients with Treacher Collins syndrome.

Project description:BACKGROUND: Treacher Collins syndrome (TCS) is one of the most severe autosomal dominant congenital disorders of craniofacial development and shows variable phenotypic expression. TCS is extremely rare, occurring with an incidence of 1 in 50.000 live births. The TCS distinguishing characteristics are represented by down slanting palpebral fissures, coloboma of the eyelid, micrognathia, microtia and other deformity of the ears, hypoplastic zygomatic arches, and macrostomia. Conductive hearing loss and cleft palate are often present. TCS results from mutations in the TCOF1 gene located on chromosome 5, which encodes a serine/alanine-rich nucleolar phospho-protein called Treacle. However, alterations in the TCOF1 gene have been implicated in only 81-93% of TCS cases. METHODS: In this study, the entire coding regions of the TCOF1 gene, including newly described exons 6A and 16A, were sequenced in 46 unrelated subjects suspected of TCS clinical indication. RESULTS: Fifteen mutations were reported, including twelve novel and three already described in 14 sporadic patients and in 3 familial cases. Moreover, seven novel polymorphisms were also described. Most of the mutations characterised were microdeletions spanning one or more nucleotides, in addition to an insertion of one nucleotide in exon 18 and a stop mutation. The deletions and the insertion described cause a premature termination of translation, resulting in a truncated protein. CONCLUSION: This study confirms that almost all the TCOF1 pathogenic mutations fall in the coding region and lead to an aberrant protein.

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Deciphering TCOF1 mutations in Chinese Treacher Collins syndrome patients: insights into pathogenesis and transcriptional disruption.

Project description:BackgroundTreacher Collins syndrome (TCS, MIM #154500), a severe congenital disorder, predominantly involves dysplasia of craniofacial bones and is characterized by features such as downslanting palpebral fissures, lower eyelid colobomas, microtia, and other craniofacial anomalies. Despite its clinical importance, the underlying pathogenic mutations in TCS remain largely uncharacterized, representing a critical knowledge gap for researchers in the field.ResultsTo address this, we performed mutation screening on a familial TCS case (trio) and 11 sporadic cases from a Chinese population. We identified 11 mutations predominantly localized to the central repeat domain (CRD) and the C-terminal domain (CTD, including the nuclear localization sequence) of TCOF1. The de novo frameshift mutation identified in the trio led to TCOF1 truncation, disrupting the central repeat domain crucial for binding transcriptional factors. Immunoprecipitation assays revealed that this pathogenic mutation attenuates the interaction between TCOF1 and transcription-related proteins, such as Pol II. Furthermore, cellular luciferase assays demonstrated that the mutation compromises the nuclear localization capability of TCOF1.ConclusionsOur findings establish TCOF1 as the primary pathogenic gene in this Chinese TCS cohort, with mutations predominantly in the CRD and CTD, thereby expanding the known mutation spectrum of TCS and informing its prevention strategies.

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Mutation analysis of TCOF1 gene in Chinese Treacher Collins syndrome patients.

Project description:BackgroundTreacher Collins syndrome (TCS) is a rare autosomal dominant or recessive disorder, that involves unique bilateral craniofacial malformations. The phenotypes of TCS are extremely diverse. Interventional surgery can improve hearing loss and facial deformity in TCS patients.MethodWe recruited seven TCS families. Variant screening in probands was performed by targeted next-generation sequencing (NGS). The variants identified were confirmed by Sanger sequencing. The pathogenicity of all the mutations was evaluated using the guidelines of the American College of Medical Genetics and Genomics (ACMG) and InterVar software.ResultsThree frameshift variants, two nonsense variants, one missense variant, and one splicing variant of TCOF1 were identified in the seven TCS probands. Five variants including c.1393C > T, c.4111 + 5G>C, c.1142delC, c.2285_2286delCT, and c.1719delG had not been previously reported. Furthermore, we report the c.149A > G variant for the first time in a Chinese TCS patient. We provided prenatal diagnosis for family 4. Proband 7 chose interventional surgery.ConclusionWe identified five novel variants in TCOF1 in Chinese patients with TCS, which expands the mutation spectrum of TCOF1 in TCS. Bone conduction hearing rehabilitation can improve hearing for TCS patients and prenatal diagnosis can provide fertility guidance for TCS families.

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Treacher Collins syndrome: unmasking the role of Tcof1/treacle.

Project description:Treacher Collins syndrome (TCS) is a rare congenital birth disorder characterized by severe craniofacial defects. The syndrome is associated with mutations in the TCOF1 gene which encodes a putative nucleolar phosphoprotein known as treacle. An animal model of the severe form of TCS, generated through mutation of the mouse homologue Tcof1 has recently revealed significant insights into the etiology and pathogenesis of TCS (Dixon and Dixon, 2004; Dixon et al., 2006; Jones et al 2008). During early embryogenesis in a TCS individual, an excessive degree of neuroepithelial apoptosis diminishes the generation of neural crest cells. Neural crest cells are a migratory stem and progenitor cell population that generates most of the tissues of the head including much of the bone, cartilage and connective tissue. It has been hypothesized that mutations in Tcof1 disrupt ribosome biogenesis to a degree that is insufficient to meet the proliferative needs of the neuroepithelium and neural crest cells. This causes nucleolar stress activation of the p53-dependent apoptotic pathway which induces neuroepithelial cell death. Interestingly however, chemical and genetic inhibition of p53 activity can block the wave of apoptosis and prevent craniofacial anomalies in Tcof1 mutant mice [Jones NC, Lynn ML, Gaudenz K, Sakai D, Aoto K, Rey JP, et al. Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nat Med 2008;14:125-33]. These findings shed new light on potential therapeutic avenues for the prevention of not only TCS but also other congenital craniofacial disorders which share a similar etiology and pathogenesis.

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Reduced transcription of TCOF1 in adult cells of Treacher Collins syndrome patients.

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Identification of a novel gross deletion of TCOF1 in a Chinese prenatal case with Treacher Collins syndrome.

Project description:BackgroundTreacher Collins syndrome (TCS) is the most common mandibulofacial dysostosis with an autosomal dominant or rarely recessive manner of inheritance. It is still challenging to make a definite diagnosis for affected fetuses with TCS only depending on the ultrasound screening. Genetic tests can contribute to the accurate diagnosis for those prenatal cases.MethodsTargeted exome sequencing was performed in a fetus of a Chinese family, who presenting an abnormal facial appearance by prenatal 2D and 3D ultrasound screening, including micrognathia, nasal bridge pit, and abnormal auricle. The result was validated with multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative PCR (qPCR).ResultsA novel 2-6 exons deletion of TCOF1 gene was identified and confirmed by the MLPA and qPCR in the fetus, which was inherited from the affected father with similar facial anomalies.ConclusionThe heterozygous deletion of 2-6 exons in TCOF1 results in the TCS of this Chinese family. Our findings not only enlarge the spectrum of mutations in TCOF1 gene, but also highlight the values of combination of ultrasound and genetics tests in diagnosis of craniofacial malformation-related diseases during perinatal period.

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Mutational Analysis of TCOF1, GSC, and HOXA2 in Patients With Treacher Collins Syndrome.

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A novel intronic TCOF1 pathogenic variant in a Chinese family with Treacher Collins syndrome.

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Gross deletions in TCOF1 are a cause of Treacher-Collins-Franceschetti syndrome.

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Two novel pathogenic variants in the TCOF1 found in two Chinese cases of Treacher Collins syndrome

Project description: Not available

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