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Articular Cartilage Development
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
Other relevant transcription factors during cartilage development include Pax1 and scleraxis (Table 2.2), which activate cartilage-specific genes (Cserjesi et al. 1995; Sosic et al. 1997). Members of the Sox protein family, specifically Sox9, Sox5, and Sox6, are also expressed in prechondrogenic cells, with Sox9 being necessary for the mesenchymal aggregation (Bi et al. 1999). This differentiation of mesenchymal cells into chondroblasts and further into chondrocytes is under the control of BMP2, BMP4 and 7, and TGF-β (Cole et al. 2003; Tickle 2003). A temporal expression profile of various transcription factors is depicted in Figure 2.11.
Familial Hyperparathyroidism
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Luigia Cinque, Alfredo Scillitani, Vito Guarnieri
Studies of patients with hypoparathyroidism and mouse models revealed that the development of parathyroid glands from endodermal cells of the third and fourth pharyngeal pouches and neural crest arising from embryonic mid- and hind-brain is coordinated by several genes encoding transcription factors including Gcm2 and other transcription factors such as Tbx1, Gata3, Sox3, Aire1, Hoxs, and Paxs. Their expression has been proved to be normal in the third pharyngeal pouch of Gcm2−/− mouse embryos and they act upstream of Gcm2 in a transcriptional regulatory cascade [121]. These studies were able to elucidate the molecular mechanism to promote the parathyroid development: cDNA microarray analysis of mice lacking Tbx1 showed downregulation of Gcm2 in the pharyngeal region, indicating that Tbx1, regulated in turn by Sonic Hedgehog (Shh), is upstream of Gcm2 [122,123].Grigorieva et al. demonstrated that GCMB is transcriptionally regulated by GATA3, a transcription factor responsible of HDR syndrome (MIM146255), that binds the promoter of the human GCMB and is implicated in the maintained differentiation and survival of parathyroid progenitor cells [124].Hoxa3 seems to be required for the initiation of Gcm2 expression in the third pharyngeal pouches. Moreover, Hoxa3 and Pax1 are required for the maintenance of Gcm2 expression [125].
A Case of Osteogenesis Imperfecta Type II With Additional Balanced Translocation t(1;20)(p13;p11.2)
Published in Fetal and Pediatric Pathology, 2019
Nasma K. Majeed, Diana Oramas, Valerie Lindgren, Steven Garzon, Dr. Elizabeth Wiley, Christopher Enakpene, Rajyasree Emmadi
The additional finding in our case is the balanced translocation. Reciprocal translocations represent one of the most common structural rearrangements observed in humans. The frequency range from 1/1000 to 1/673 [18]. Reciprocal translocations occur when two different chromosomes exchange segments and are more frequently inherited (70%) rather than de novo (30%) [19]. Literature suggests a more likely paternal source of such inheritance [20]. Although individuals who carry truly balanced reciprocal translocations are themselves usually clinically normal, they do have an increased risk for having children with intellectual disability and congenital anomalies, infertility or multiple spontaneous abortions due to unbalanced segregation at meiosis of the chromosomes involved. A gene disrupted or dysregulated at the breakpoint of the translocation may cause additional findings in the balanced carrier and offspring. Because the parents of this fetus have not been studied, we do not know whether the translocation is de novo or inherited. For the same reason, we also do not know if any gonadal mosaicism may have been a factor. Microarray analysis of the patient’s DNA did not reveal any losses or gains at the breakpoints. While there are no genes in the regions of the breakpoints that are candidates for involvement in OI, two genes in the 1p13 locus, CSF1 and NOTCH2 and the PAX1 gene at the 20p11.2 locus, are of speculative interest in this patient. The CSF1 gene encodes macrophage colony-stimulating factor, a critical cytokine for osteoclast formation and survival and has been identified as the strongest candidate gene for susceptibility for Paget’s disease of the bone [21]. Abnormalities of the NOTCH2 gene have been associated with Hadju–Cheney syndrome, in one case showing skeletal abnormalities including wormian bones, vertebral abnormalities, and serpentine fibula [22]. The PAX1 gene is a member of the paired box family of transcription factors, which play essential roles in pattern formation during embryogenesis and the development of the vertebral column [23]. This case emphasizes that the DNA abnormalities of OI type II are complex and perhaps not fully elucidated. Therefore, when prenatal findings suggest skeletal dysplasia, providers should be aware of the association between OI type II and c.3065G > T transversion in exon 42 of the COL1A1, to provide prompt postmortem diagnosis and proper pre-natal counseling with tailored follow up for future pregnancies. Nonetheless, the clinical significance of this mutation and translocation in future offspring remains uncertain; and, hence prospective follow up of these patients is paramount to answer this question.
PAX1 and SEPT9 methylation analyses in cervical exfoliated cells are highly efficient for detecting cervical (pre)cancer in hrHPV-positive women
Published in Journal of Obstetrics and Gynaecology, 2023
Lulu He, Xiping Luo, Qiaowen Bu, Jing Jin, Shuai Zhou, Shaoyi He, Liang Zhang, Yu Lin, Xiaoshan Hong
Compelling evidence has demonstrated that aberrant DNA methylation is one of the earliest events during the tumorigenic process and often occurs in the precursor lesions of human cancers, including genital tract cancers (Tian et al.2017, Kremer et al.2021). It has been reported that PAX1 and SEPT9 act as tumour suppressor genes and are involved in numerous cellular processes of hypermethylation during the carcinogenesis process (Connolly et al.2011, Wu et al.2022). A series of studies have detected PAX1 and SEPT9 methylation in a broad spectrum of tumour tissues including cervical cancer tissue (Jiao et al.2019, Lyu et al.2020, Li et al.2021). Some studies have highlighted the potential of PAX1 methylation in cervical cancer screening (Fang et al.2019, Liang et al.2020). However, to the best of our knowledge, this study was the first to investigate the diagnostic capacity of SEPT9 methylation for detecting cervical (pre)cancer in cervical exfoliated cells from hrHPV-positive women. Liu et al. (2020) and Jiao et al. (2019) found that the methylation levels of PAX1 and SEPT9 were elevated with worsening cervical centercancer, closely resembling our results. A review reported on a variety of methylation markers that were clinically evaluated for detecting cervical (pre)cancer, with sensitivity values of 55.00–88.00% and specificity values of 60.00–91.00%, which were consistent with this study (Luttmer et al.2016). In the present study, both PAX1 and SEPT9 were hypermethylated in all cervical cancer exfoliated cells, with higher methylation frequencies as compared with other genes reported being hypermethylated in cervical cancer (Xu et al.2019, Li et al.2021). The methylation levels of PAX1 and SEPT9 in cervical cancer exfoliated cells were the highest, which suggested that even when the methylation test was set at a very high threshold, the probability of missing cervical cancer was small. It is worth noting that, in this study, 22 cervical cancers with PAX1 and SEPT9 hypermethylation also included special types of cervical cancer, which were prone to occur in young women with poor prognosis and no significant association with HPV (Pal et al.2015). Recent research have indicated that HPV-negative cervical cancers may represent a biologically distinct subset of tumours, relying on a distinct pathogenetic pathway and carrying a poorer prognosis than HPV-positive cervical cancers (Arezzo et al.2021). Another study revealed the adoption of HPV testing alone would miss the diagnosis of 10–15% HPV-negative HSIL (Bogani et al.2021). From this perspective, the analyses of PAX1 and SEPT9 methylation levels are both conducive to early detection and treatment of special types of cervical (pre)cancer and HPV-negative cervical (pre)cancer, which is helpful for fertility preservation.