Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: Functional differentiation from Muenke coronal synostosis syndrome

Philipps University of Marburg, Marburg, Hesse, Germany
European Journal of HumanGenetics (Impact Factor: 4.35). 02/2006; 14(1):39-48. DOI: 10.1038/sj.ejhg.5201507
Source: PubMed


The Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with uni- or bilateral coronal synostosis and mild limb deformities. It is caused by loss-of-function mutations of the TWIST 1 gene. In an attempt to delineate functional features separating SCS from Muenke's syndrome, we screened patients presenting with coronal suture synostosis for mutations in the TWIST 1 gene, and for the Pro250Arg mutation in FGFR3. Within a total of 124 independent pedigrees, 39 (71 patients) were identified to carry 25 different mutations of TWIST 1 including 14 novel mutations, to which six whole gene deletions were added. The 71 patients were compared with 42 subjects from 24 pedigrees carrying the Pro250Arg mutation in FGFR3 and 65 subjects from 61 pedigrees without a detectable mutation. Classical SCS associated with a TWIST 1 mutation could be separated phenotypically from the Muenke phenotype on the basis of the following features: low-set frontal hairline, gross ptosis of eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and hallux valgus or broad great toe with bifid distal phalanx. Functional differences were even more important: intracranial hypertension as a consequence of early progressive multisutural fusion was a significant problem in SCS only, while mental delay and sensorineural hearing loss were associated with the Muenke's syndrome. Contrary to previous reports, SCS patients with complete loss of one TWIST allele showed normal mental development.

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Available from: Wolfram Kress, Mar 12, 2014
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    • "The mutations themselves are mostly missenses , such as in the case of FGFRs, but in the TWIST gene most anomalies are caused by nonsense changes and 21 bp duplications and complete deletions (Johnson et al., 1998; Kress et al., 2006; Wilkie, 1997). However, missense substitutions have been found in the TWIST protein in sagittal synostotic cases (Bialek et al., 2004; Kress et al., 2006), which suggests that these genes have an important role not only in syndromic craniosynostoses, and might have an influence on nonsyndromic cases and in later ossification during normal development as well. Testing sporadic, nonsyndromic cases seems to be a much greater challenge, while in most individuals with sagittal, metopic, or lambdoid synostoses—with the occasional exception of some—the efficiency of the known genetic diagnoses was close to zero (Wilkie et al., 2007). "
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    ABSTRACT: The primary objective of this study was to perform new, relevant information about cranial suture closure in adults. Single nucleotide polymorphisms (SNPs) in targeted genes were examined, which encode factors that play an important role in cranial suture development and maintenance. Our hypothesis was that some of these genes and polymorphisms can influence the cranial suture obliteration status in adulthood as well. Ossification of cranial sutures was ascertained according to Meindl and Lovejoy's vault system (1985: Am J Phys Anthropol 68(1):57-66), and peripheral blood samples were collected during autopsy procedure of 106 individuals at the Department of Forensic and Insurance Medicine, Semmelweis University, Hungary. Genotyping of SNPs was conducted using competitive allele-specific polymerase chain reaction KASPar chemistry. Multivariate linear models were used to test whether SNP polymorphism of the investigated genes has a significant effect on the ectocranial suture synostosis in adults. The msh homeobox 1 (MSX1): rs3821947 polymorphism showed significant association with the extent of suture obliteration. Cranial suture closure in adults is a complex, multifactorial process. According to previous results MSX1 has a role in calvarial bone development and it has an effect on sutural mesenchyme in latter postnatal stages. Our results demonstrate MSX1 effects on suture obliteration in adulthood. These findings represent new, relevant information indicating that genetic background can have an impact on cranial suture closure in adults. Am. J. Hum. Biol., 2013. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2013 · American Journal of Human Biology
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    • "TWIST1 plays a key role in the regulation of embryogenesis, gastrulation and mesoderm formation during early embryonic development of Drosophila and many other species [4,5]. An autosomal mutation pattern in the TWIST1 gene leads to Saethre-Chotzen syndrome, a genetic condition characterized by premature fusion of skull bones affecting symmetrical growth of the head and face [6]. In children, TWIST1 protein is involved in adequate maturation of the skull and spine bones and normal development of arms and hind legs. "
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    ABSTRACT: Introduction The TWIST homolog 1 (TWIST1) is a transcription factor that induces epithelial to mesenchymal transition (EMT), a key process in metastasis. The purpose of this study was to investigate whether TWIST1 expression predicts disease progression in a large breast cancer cohort with long-term clinical follow-up, and to reveal the biology related to TWIST1 mediated disease progression. Methods TWIST1 mRNA expression level was analyzed by quantitative real-time reverse polymerase chain reaction (RT-PCR) in 1,427 primary breast cancers. In uni- and multivariate analysis using Cox regression, TWIST1 mRNA expression level was associated with metastasis-free survival (MFS), disease-free survival (DFS) and overall survival (OS). Separate analyses in lymph node-negative patients (LNN, n = 778) who did not receive adjuvant systemic therapy, before and after stratification into estrogen receptor (ER)-positive (n = 552) and ER-negative (n = 226) disease, were also performed. The association of TWIST1 mRNA with survival endpoints was assessed using Kaplan-Meier analysis. Using gene expression arrays, genes showing a significant Spearman rank correlation with TWIST1 were used to identify overrepresented Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG)-annotated biological pathways. Results Increased mRNA expression level of TWIST1 analyzed as a continuous variable in both uni- and multivariate analysis was associated with shorter MFS in all patients (hazard ratio (HR): 1.17, 95% confidence interval, (95% CI):1.09 to 1.26; and HR: 1.17, 95% CI: 1.08 to 1.26; respectively), in LNN patients (HR: 1.22, 95% CI: 1.09 to 1.36; and HR: 1.21, 95% CI: 1.07 to 1.36; respectively) and in the ER-positive subgroup of LNN patients (HR: 1.34, 95% CI: 1.17 to 1.53; and HR: 1.32, 95% CI: 1.14 to 1.53; respectively). Similarly, high TWIST1 expression was associated with shorter DFS and OS in all patients and in the LNN/ER-positive subgroup. In contrast, no association of TWIST1 mRNA expression with MFS, DFS or OS was observed in ER-negative patients. Genes highly correlated with TWIST1 were significantly enriched for cell adhesion and ECM-related signaling pathways. Furthermore, TWIST1 mRNA was highly expressed in tumor stroma and positively related to tumor stromal content (P <0.001). Conclusions TWIST1 mRNA expression is an independent prognostic factor for poor prognosis in LNN/ER-positive breast cancer. The biological associations suggest an involvement of the tumor microenvironment in TWIST1's adverse role in breast cancer.
    Full-text · Article · Sep 2012 · Breast cancer research: BCR
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    • "above, they were chosen for their high heterozygosity, and for their previous linkage to Class III malocclusion (Yamaguchi et al., 2005) or proximity to candidate regions to skeletal disorders (Stein et al., 2004; Yoshida et al., 2004; Yamaguchi et al., 2005; Freitas et al., 2006; Jacob et al., 2006; Kress et al., 2006; Rump et al., 2006; Stevens and Roeder, 2006). D1S234 is located relatively close to RUNX3, D6S1689 to RUNX2, D4S3038 to FGFR3, D7S503 to TWIST, and D10S1483 to FGFR2. "
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    ABSTRACT: The role played by genetic components in the etiology of the Class III phenotype, a class of dental malocclusion, is not yet understood. Regions that may be related to the development of Class III malocclusion have been suggested previously. The aim of this study was to search for genetic linkage with 6 microsatellite markers (D1S234, D4S3038, D6S1689, D7S503, D10S1483, and D19S566), near previously proposed candidate regions for Class III. We performed a two-point parametric linkage analysis for 42 affected individuals from 10 Brazilian families with a positive Class III malocclusion segregation. Analysis of our data indicated that there was no evidence for linkage of any of the 6 microsatellite markers to a Class III locus at = zero, with data supporting exclusion for 5 of the 6 markers evaluated. The present work reinforces that Class III is likely to demonstrate locus heterogeneity, and there is a dependency of the genetic background of the population in linkage studies.
    Full-text · Article · Aug 2011 · Journal of dental research
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