• Journal of Genetic Medicine
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• v.13 no.1
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• pp.31-35
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• 2016

Antley-Bixler syndrome (ABS) is a rare form of syndromic craniosynostosis with additional systemic synostosis, including radiohumeral or radioulnar synostosis. Another characteristic feature of ABS is mid-facial hypoplasia that leads to airway narrowing after birth. ABS is associated with mutations in the FGFR2 and POR genes. Patients with POR mutations present with either skeletal manifestations or congenital adrenal hyperplasia with ambiguous genitalia. We report here two cases of ABS caused by mutations in FGFR2 and POR. Although the patients had craniosynostosis and radiohumeral synostosis in common and cranioplasty was performed in both cases, the male with POR mutations showed an elevated level of $17{\alpha}$-hydroxyprogesterone during newborn screening and was diagnosed with congenital adrenal hyperplasia by adrenocorticotropic hormone stimulation. This patient has been treated with hydrocortisone and fludrocortisone. He had no ambiguous genitalia but had bilateral cryptorchidism. On the other hand, the female with the FGFR2 mutation showed severe clinical manifestations: upper airway narrowing leading to tracheostomy, kyphosis of the cervical spine, and coccyx deformity. ABS shows locus heterogeneity, and mutations in two different genes can cause similar craniofacial and skeletal phenotypes. Because the long-term outcomes and inheritance patterns of the disease differ markedly, depending on the causative mutation, early molecular genetic testing is helpful.

• Journal of the Korean Society of Laryngology, Phoniatrics and Logopedics
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• v.33 no.1
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• pp.50-53
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• 2022

A case is presented to show tracheal cartilaginous sleeve in Antley-Bixler syndrome, which is the second case to be reported so far. In this patient, W290C mutation in FGFR2, the mutation previously known to cause Pfeiffer syndrome, was newly identified. After receiving tracheostomy, the patient recovered from repetitive respiratory distress, and retrieved normal respiratory function. Thorough airway examination and active surgical management such as tracheostomy is necessary in children with syndromic craniosynostosis, including Antley-Bixler syndrome.

• Molecules and Cells
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• v.43 no.2
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• pp.168-175
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• 2020

Runx2 is an essential transcription factor for skeletal development. It is expressed in multipotent mesenchymal cells, osteoblast-lineage cells, and chondrocytes. Runx2 plays a major role in chondrocyte maturation, and Runx3 is partly involved. Runx2 regulates chondrocyte proliferation by directly regulating Ihh expression. It also determines whether chondrocytes become those that form transient cartilage or permanent cartilage, and functions in the pathogenesis of osteoarthritis. Runx2 is essential for osteoblast differentiation and is required for the proliferation of osteoprogenitors. Ihh is required for Runx2 expression in osteoprogenitors, and hedgehog signaling and Runx2 induce the differentiation of osteoprogenitors to preosteoblasts in endochondral bone. Runx2 induces Sp7 expression, and Runx2, Sp7, and canonical Wnt signaling are required for the differentiation of preosteoblasts to immature osteoblasts. It also induces the proliferation of osteoprogenitors by directly regulating the expression of Fgfr2 and Fgfr3. Furthermore, Runx2 induces the proliferation of mesenchymal cells and their commitment into osteoblast-lineage cells through the induction of hedgehog (Gli1, Ptch1, Ihh), Fgf (Fgfr2, Fgfr3), Wnt (Tcf7, Wnt10b), and Pthlh (Pth1r) signaling pathway gene expression in calvaria, and more than a half-dosage of Runx2 is required for their expression. This is a major cause of cleidocranial dysplasia, which is caused by heterozygous mutation of RUNX2. Cbfb, which is a co-transcription factor that forms a heterodimer with Runx2, enhances DNA binding of Runx2 and stabilizes Runx2 protein by inhibiting its ubiquitination. Thus, Runx2/Cbfb regulates the proliferation and differentiation of chondrocytes and osteoblast-lineage cells by activating multiple signaling pathways and via their reciprocal regulation.

• Journal of the Korean Society of Radiology
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• v.84 no.4
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• pp.970-976
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• 2023

This study reports on diffuse leptomeningeal glioneuronal tumor (DL-GNT) in a 29- year-old male. DL-GNT is a rare central nervous system (CNS) tumor mostly seen in children and only few cases have been reported in adult patients. Our patient presented with a chronic headache that lasted for five months. MR imaging showed mild hydrocephalus, multiple rim-enhancing nodular lesions in the suprasellar cistern, diffuse leptomeningeal enhancement in the lumbosacral area, and multiple small non-enhancing cyst-appearing lesions not suppressed on fluid attenuated inversion recovery (FLAIR) images in the bilateral basal ganglia, thalami, and cerebral hemispheres. Under the impression of germ cell tumor with leptomeningeal seeding, the patient underwent trans-sphenoidal tumor removal. DL-GNT was pathologically confirmed and FGFR1 mutation was detected through a next-generation sequencing test. In conclusion, a combination of leptomeningeal enhancement and multiple parenchymal non-enhancing cyst-appearing lesions not suppressed on FLAIR images may be helpful for differential diagnosis despite overlapping imaging features with many other CNS diseases that have leptomeningeal enhancement.

• Clinical and Experimental Reproductive Medicine
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• v.40 no.1
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• pp.42-46
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• 2013

Hypochondroplasia (HCH) is an autosomal dominant inherited skeletal dysplasia, usually caused by a heterozygous mutation in the fibroblast growth factor receptor 3 gene (FGFR3). A 27-year-old HCH woman with a history of two consecutive abortions of HCH-affected fetuses visited our clinic for preimplantation genetic diagnosis (PGD). We confirmed the mutation in the proband (FGFR3:c.1620C>A, p.N540K), and established a nested allele-specific PCR and sequence analysis for PGD using single lymphocyte cells. We performed this molecular genetic analysis to detect the presence of mutation among 20 blastomeres from 18 different embryos, and selected 9 embryos with the wild-type sequence (FGFR3:c.1620C). A successful pregnancy was achieved through a frozen-thawed cycle and resulted in the full-term birth of a normal neonate. To the best of our knowledge, this is the first report of a successful pregnancy and birth using single-cell allele-specific PCR and sequencing for PGD in an HCH patient.

• Journal of Genetic Medicine
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• v.13 no.1
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• pp.46-50
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• 2016

Achondroplasia and hypochondroplasia are the two most common forms of short-limb dwarfism. They are autosomal dominant diseases that are characterized by a rhizomelic shortening of the limbs, large head with frontal bossing, hypoplasia of the mid-face, genu varum and trident hands. Mutations in the fibroblast growth factor receptor-3 (FGFR3) gene, which is located on chromosome 4p16.3, have been reported to cause achondroplasia and hypochondroplasia. More than 98% of achondroplasia cases are caused by the G380R mutation (c.1138G>A or c.1138G>C). In contrast, the N540K mutation (c.1620C>A) is detected in 60-65% of hypochondroplasia cases. Tests for common mutations are often unable to detect the mutation in patients with a clinical diagnosis of hypochondroplasia. In this study, we presented a case of familial hypochondroplasia with a rare mutation in FGFR3 identified by next generation sequencing.

• Reproductive and Developmental Biology
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• v.30 no.2
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• pp.125-133
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• 2006

This study was conducted to detect the apoptosis incidence in blastocysts and to compare the abundance of Bax, Bcl2L1, VEGF and FGFR2 in in vitro fertilized (IVF), parthenogenetic (PAT) and nuclear transfer (NT) embryos. Oocytes matured for 40 hr were enucleated and reconstructed with confluenced fetal fibroblasts (FFs) derived from a ${\sim}45$ day fetus. Reconstructed eggs were then fused with 2 DC pulses (2.0 kV/cm, $30{\mu}sec$) and cultured with $7.5{\mu}g/ml$ cytochalasin B for 3 hr. Parthenotes (PAT) were produced with the same electric strength and culture for NT eggs. The embryos were cultured in NCSU-23 medium at $39^{\circ}C,\;5%\;CO_2,\;5%\l;O_2$ in air. In 3 runs, set of 10 embryos at the 4-cell to blastocyst stages were used to extract total RNA for analyzing the gene expression patterns of pro-apoptotic (Bax), anti-apoptotic (Bcl2L1), vasculogenesis (VEGF), implantation (FGFR2III) using real-time quantitative PCR. Cleavage and blastocyst rates were significantly higher (P<0.05) in IVF and PAT ($79.3{\pm}8.5\;and\;25.5{\pm}6.1,\;and\;85.0{\pm}6.4\;and\;38.6{\pm}5.5$, respectively)than NT counterparts ($65.1{\pm}5.2\;and\;15.6{\pm}3.0$, respectively). Significantly higher (P<0.05) total cells were observed in IVF controls and PAT ($34.7{\pm}5.8\;and\;38.1{\pm}4.1$) than NT embryos ($24.8{\pm}3.2$). Apoptosis index was significantly lower (P<0.05) in IVF than NT embryos. The Relative abundances (RA) of Bax and VEGF were significantly higher (P<0.05) at blastocyst stage in NT than IVF control. The RA of Bcl2L1 and FGFR2III were significantly higher (P<0.05) at blastocyst stage in IVF than NT. The present study observed the abnormal gene expressions in NT embryos at various developmental stages, suggesting certain clues to find out the cause of the low efficiency of NT to term.

• Journal of Gastric Cancer
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• v.20 no.1
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• pp.29-40
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• 2020

Purpose: Gastrointestinal stromal tumors (GISTs) frequently harbor activating gene mutations in either KIT or platelet-derived growth factor receptor A (PDGFRA) and are highly responsive to several selective tyrosine kinase inhibitors. In this study, a targeted next-generation sequencing (NGS) assay with an Oncomine Focus Assay (OFA) panel was used for the genetic characterization of molecular targets in 30 Korean patients with GIST. Materials and Methods: Using the OFA that enables rapid and simultaneous detection of hotspots, single nucleotide variants (SNVs), insertion and deletions (Indels), copy number variants (CNVs), and gene fusions across 52 genes relevant to solid tumors, targeted NGS was performed using genomic DNA extracted from formalin-fixed and paraffin-embedded samples of 30 GISTs. Results: Forty-three hotspot/other likely pathogenic variants (33 SNVs, 8 Indels, and 2 amplifications) in 16 genes were identified in 26 of the 30 GISTs. KIT variants were most frequent (44%, 19/43), followed by 6 variants in PIK3CA, 3 in PDGFRA, 2 each in JAK1 and EGFR, and 1 each in AKT1, ALK, CCND1, CTNNB1, FGFR3, FGFR4, GNA11, GNAQ, JAK3, MET, and SMO. Based on the mutation types, majority of the variants carried missense mutations (60%, 26/43), followed by 8 frameshifts, 6 nonsense, 1 stop-loss, and 2 amplifications. Conclusions: Our study confirmed the advantage of using targeted NGS with a cancer gene panel to efficiently identify mutations associated with GISTs. These findings may provide a molecular genetic basis for developing new drugs targeting these gene mutations for GIST therapy.

• Journal of the korean academy of Pediatric Dentistry
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• v.36 no.1
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• pp.133-138
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• 2009

Crouzon syndrome is a rare disease, first decribed by Crouzon in 1912. This syndrome is cuased by mutations in the FGFR2 gene, which is mapped to chromosome locus 10q25-10q26. The condition occurs in about 1 of every 25,000 birth and is inherited as an autosomal dominant trait. We experienced a case of Crouzon's disease in a 9-year-old-female child. Physical examination revealed craniosynostosis, hypertelorism, exophthalmos, hypoplastic maxilla and a relative mandibular prognathism. The purpose of this study is to report the dental and medical characteristics of the patient and review the literatures of Crouzon syndrome.

• Biomedical Science Letters
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• v.23 no.3
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• pp.238-250
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• 2017

Patient's primary tumor-derived tumor cell lines likely represent ideal tools for human tumor biology in vitro and in vivo. Here, we describe eight human gastric carcinoma cell lines derived from established tumors in vivo upon subcutaneous transplantation of primary gastric carcinoma specimens in BALB/c nude mice. These xenografted gastric tumor cell lines (GTX) displayed close similarity with primary gastric tumor tissues in their in vivo growth pattern and genomic alterations. GTX-085 cells were resistant to cisplatin, while GTX-087 was the most sensitive cell line. GTX-085 was the only cell line showing a metastatic potential. Epithelial cell adhesion molecule (EPCAM) expression was especially strong in all tissue samples, as well as in cell cultures. GTX-139, the largest tumor graft obtained after injection, displayed distinct expression of CD44v6, fibroblast growth factor receptor 2 (FGFR2), and prominin 1 (PROM1, also known as CD133). In summary, we established eight xenograft gastric cancer cell lines from gastric cancer patient tissues, with their histological and molecular features consistent with those of the primary tumors. The established GTX cell lines will enable future studies of their responses to various treatments for gastric cancer.