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\"A moving memoir from the mother of a child with Treacher Collins Syndrome, with a foreword by R.J. Palacio, author of Wonder\"-- Provided by publisher.

Treacher Collins syndrome (TCS) is associated with abnormal differentiation of the first and second pharyngeal arches, occurring during fetal development. Features of TCS include microtia with conductive hearing loss, slanting palpebral fissures with possibly coloboma of the lateral part of lower eyelids, midface hypoplasia, micrognathia as well as sporadically cleft palate and choanal atresia or stenosis. TCS occurs in the general population at a frequency of 1 in 50,000 live births. Four subtypes of Treacher Collins syndrome exist. TCS can be caused by pathogenic variants in the TCOF1, POLR1D, POLR1C and POLR1B genes. Genetically, the TCOF1 gene contains 27 exons which encodes the Treacle protein. In TCOF1, over 200 pathogenic variants have been identified, of which most are deletions leading to a frame-shift, that result in the formation of a termination codon. In the presented article, we review the genetics and phenotype of TCS as well as the management and surgical procedures utilized for treatment.

Birth defects are the leading cause of infant mortality, and most inborn errors of development are multifactorial in origin resulting from complex gene-environment interactions. Definition of specific gene-environment interactions in the etiology and pathogenesis of congenital disorders is critically needed in the absence of genotype-phenotype correlation but is challenging. This is particularly true for congenital craniofacial anomalies, which account for approximately one-third of all birth defects, as they typically exhibit considerable inter- and intrafamilial variability. A classic example of this is Treacher Collins syndrome (TCS), which, although primarily caused by mutations in treacle ribosome biogenesis factor 1 (TCOF1), is characterized by considerable variability in the severity of mandibulofacial dysostosis. Here, we describe the genetic and environmental factors with converging effects that mechanistically contribute to the etiology and pathogenesis of craniofacial variation in this rare congenital disorder. We discovered in Tcof1+/- mouse models of TCS that the combination of different endogenous levels of Tcof1 (also known as treacle) protein and ROS within distinct genetic backgrounds correlated with TCS phenotype severity. Furthermore, geometric morphometric analyses revealed that genotype largely determines the craniofacial shape but that redox status determines the size of individual bones. Taken together, our results highlight the roles of ROS and genomic instability in modulating the variability and phenotype severity of craniofacial anomalies.

Craniofacial anomalies account for approximately one-third of all birth defects and are a significant cause of infant mortality. Since the majority of the bones, cartilage and connective tissues that comprise the head and face are derived from a multipotent migratory progenitor cell population called the neural crest, craniofacial disorders are typically attributed to defects in neural crest cell development. Treacher Collins syndrome (TCS) is a disorder of craniofacial development and although TCS arises primarily through autosomal dominant mutations in TCOF1 , no clear genotype–phenotype correlation has been documented. Here we show that Tcof1 haploinsufficiency results in oxidative stress-induced DNA damage and neuroepithelial cell death. Consistent with this discovery, maternal treatment with antioxidants minimizes cell death in the neuroepithelium and substantially ameliorates or prevents the pathogenesis of craniofacial anomalies in Tcof1 +/− mice. Thus maternal antioxidant dietary supplementation may provide an avenue for protection against the pathogenesis of TCS and similar neurocristopathies. The TCOF1 gene is mutated in Treacher Collin's syndrome, a congenital craniofacial syndrome. Here, the authors show that Tcof1 loss-of-function results in oxidative stress induced DNA damage and neuroepithelial cell death, and addition of antioxidants to pregnant mutant mice protected against these defects.

Mutations associated with Treacher Collins syndrome perturb the subnuclear localization of an RNA helicase involved in ribosome biogenesis through activation of p53 protein, illustrating how disruption in general regulators that compromise nucleolar homeostasis can result in tissue-selective malformations. RNA-related regulation in craniofacial development Many craniofacial disorders are due to defects in cranial neural crest cells, a cell type that gives rise to the majority of facial structures during embryogenesis. Yet, many of the genetic defects underlying these disorders are heterozygous mutations in general transcription and translation regulators, which are not tissue-specific. Why cranial neural crest cells are more sensitive than others to these mutations during development is not well understood. Joanna Wysocka and colleagues show that mutations associated with Treacher Collins syndrome perturb the subnuclear localization of an RNA helicase involved in ribosome biogenesis, and that this effect occurs specifically in cranial neural crest cells. This protein relocalization process, which involves the activation of p53, impairs ribosome biogenesis and causes craniofacial defects. Many craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as transcription or ribosome biogenesis 1 , 2 . Although it is understood that many of these malformations are a consequence of defects in cranial neural crest cells, a cell type that gives rise to most of the facial structures during embryogenesis 3 , 4 , the mechanism underlying cell-type selectivity of these defects remains largely unknown. By exploring molecular functions of DDX21, a DEAD-box RNA helicase involved in control of both RNA polymerase (Pol) I- and II-dependent transcriptional arms of ribosome biogenesis 5 , we uncovered a previously unappreciated mechanism linking nucleolar dysfunction, ribosomal DNA (rDNA) damage, and craniofacial malformations. Here we demonstrate that genetic perturbations associated with Treacher Collins syndrome, a craniofacial disorder caused by heterozygous mutations in components of the Pol I transcriptional machinery or its cofactor TCOF1 (ref. 1 ), lead to relocalization of DDX21 from the nucleolus to the nucleoplasm, its loss from the chromatin targets, as well as inhibition of rRNA processing and downregulation of ribosomal protein gene transcription. These effects are cell-type-selective, cell-autonomous, and involve activation of p53 tumour-suppressor protein. We further show that cranial neural crest cells are sensitized to p53-mediated apoptosis, but blocking DDX21 loss from the nucleolus and chromatin rescues both the susceptibility to apoptosis and the craniofacial phenotypes associated with Treacher Collins syndrome. This mechanism is not restricted to cranial neural crest cells, as blood formation is also hypersensitive to loss of DDX21 functions. Accordingly, ribosomal gene perturbations associated with Diamond–Blackfan anaemia disrupt DDX21 localization. At the molecular level, we demonstrate that impaired rRNA synthesis elicits a DNA damage response, and that rDNA damage results in tissue-selective and dosage-dependent effects on craniofacial development. Taken together, our findings illustrate how disruption in general regulators that compromise nucleolar homeostasis can result in tissue-selective malformations.

Introduction Treacher Collins syndrome type 2 (TCS2; OMIM# 613717) is a rare genetic disorder of craniofacial development caused by pathogenic variants in the POLR1D gene. The characteristic clinical features include downward-slanting palpebral fissures, micrognathia, hypoplastic zygomatic arches, lower eyelid coloboma, and malformations of the external and middle ears. Case presentation In this study, we report a 2-year-and-3-month-old male of Miao ethnicity with TCS2 caused by a novel heterozygous pathogenic POLR1D variant (NM_015972.4: c.220dup, p.His74ProfsTer8), inherited from his unaffected father. He presented with downward slanting of bilateral palpebral fissures, low-set ears, and microretrognathia, along with middle ear deformities, both confirmed by CT with 3D reconstruction, accompanied by conductive hearing loss. During the neonatal period, he exhibited severe neonatal airway compromise due to combined tongue-based obstruction and laryngomalacia, necessitating a tracheostomy. Based on the above clinical manifestations and genotype, he met the diagnosis of TCS2. The tracheostomy tube was successfully decannulated at approximately 10 months of age. His prognosis was good. Conclusion This study expands the mutational spectrum of POLR1D -related TCS2 and underscores the vital role of multidisciplinary airway intervention in severe presentations. As an exceptionally rare disorder, this case provides crucial genotype-phenotype correlations that advance both clinical management strategies and molecular understanding of TCS2 pathogenesis.

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Craniosynostosis is a congenital condition characterized by the premature fusion of the craniofacial sutures. The Crouzon mouse (Fgfr2cC342Y/+) is a well-established model of this condition which shows premature fusion of the coronal suture. Our group has recently shown that postnatal, cyclic loading can potentially rescue the coronal suture and normalize skull morphology in Crouzon mice. This study aimed to investigate the underlying biological mechanism of the treatment. Wild-type (WT) and Crouzon (MUT) mice underwent in vivo loading sessions. Loading did not significantly affect skull shape. The patency across the coronal suture did not change between treated and untreated MUT animals. Orientation and coherence of the coronal suture collagen fibres were statistically different when comparing WT untreated with MUT untreated and WT treated with MUT treated. Treatment increases the number of proliferative cells in both the WT and MUT sutures compared to their untreated counterparts. The mechanobiological mechanisms driving the differences need further investigation into molecular mechanotransduction pathways. Understanding the biological principles affected during bone loading, a more refined cyclical bone loading protocol can be developed and refined for potential clinical use.

Treacle ribosome biogenesis factor 1 ( TCOF1 ) is responsible for about 80% of mandibular dysostosis (MD) cases. We have formerly identified a correlation between TCOF1 and CNBP (CCHC-type zinc finger nucleic acid binding protein) expression in human mesenchymal cells. Given the established role of CNBP in gene regulation during rostral development, we explored the potential for CNBP to modulate TCOF1 transcription. Computational analysis for CNBP binding sites (CNBP-BSs) in the TCOF1 promoter revealed several putative binding sites, two of which (Hs791 and Hs2160) overlap with putative G-quadruplex (G4) sequences (PQSs). We validated the folding of these PQSs measuring circular dichroism and fluorescence of appropriate synthetic oligonucleotides. In vitro studies confirmed binding of purified CNBP to the target PQSs (both folded as G4 and unfolded) with K d values in the nM range. ChIP assays conducted in HeLa cells chromatin detected the CNBP binding to TCOF1 promoter. Transient transfections of HEK293 cells revealed that Hs2160 cloned upstream SV40 promoter increased transcription of downstream firefly luciferase reporter gene. We also detected a CNBP-BS and PQS (Dr2393) in the zebrafish TCOF1 orthologue promoter ( nolc1 ). Disrupting this G4 in zebrafish embryos by microinjecting DNA antisense oligonucleotides complementary to Dr2393 reduced the transcription of nolc1 and recapitulated the craniofacial anomalies characteristic of Treacher Collins Syndrome. Both cnbp overexpression and Morpholino-mediated knockdown in zebrafish induced nolc1 transcription. These results suggest that CNBP modulates the transcriptional expression of TCOF1 through a mechanism involving G-quadruplex folding/unfolding, and that this regulation is active in vertebrates as distantly related as bony fish and humans. These findings may have implications for understanding and treating MD.

The acrofacial dysostoses (AFD) are a genetically heterogeneous group of inherited disorders with craniofacial and limb abnormalities. Rodriguez syndrome is a severe, usually perinatal lethal AFD, characterized by severe retrognathia, oligodactyly and lower limb abnormalities. Rodriguez syndrome has been proposed to be a severe form of Nager syndrome, a non-lethal AFD that results from mutations in SF3B4, a component of the U2 small nuclear ribonucleoprotein particle (U2 snRNP). Furthermore, a case with a phenotype intermediate between Rodriguez and Nager syndromes has been shown to have an SF3B4 mutation. We identified heterozygosity for SF3B4 mutations in Rodriguez syndrome, confirming that the phenotype is a dominant disorder that is allelic with Nager syndrome. The mutations led to reduced SF3B4 synthesis and defects in mRNA splicing, primarily exon skipping. The mutations also led to reduced expression in growth plate chondrocytes of target genes, including the DLX5, DLX6, SOX9, and SOX6 transcription factor genes, which are known to be important for skeletal development. These data provide mechanistic insight toward understanding how SF3B4 mutations lead to the skeletal abnormalities observed in the acrofacial dysostoses.