• BMB Reports
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• 제52권12호
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• pp.689-694
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• 2019

Ethical and safety issues have rendered mesenchymal stem cells (MSCs) popular candidates in regenerative medicine, but their therapeutic capacity is lower than that of induced pluripotent stem cells (iPSCs). This study compared original, dental tissue-derived MSCs with re-differentiated MSCs from iPSCs (iPS-MSCs). CD marker expression in iPS-MSCs was similar to original MSCs. iPS-MSCs expressed higher in pluripotent genes, but lower levels in mesodermal genes than MSCs. In addition, iPS-MSCs did not form teratomas. All iPSCs carried mtDNA mutations; some shared with original MSCs and others not previously detected therein. Shared mutations were synonymous, while novel mutations were non-synonymous or located on RNA-encoding genes. iPS-MSCs also harbored mtDNA mutations transmitted from iPSCs. Selected iPS-MSCs displayed lower mitochondrial respiration than original MSCs. In conclusion, screening for mtDNA mutations in iPSC lines for iPS-MSCs can identify mutation-free cell lines for therapeutic applications.

• Genomics & Informatics
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• 제18권4호
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• pp.44.1-44.7
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• 2020

The severity of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), greatly varies from patient to patient. In the present study, we explored and compared mutation profiles of SARS-CoV-2 isolated from mildly affected and severely affected COVID-19 patients in order to explore any relationship between mutation profile and disease severity. Genomic sequences of SARS-CoV-2 were downloaded from Global Initiative on Sharing Avian Influenza Data (GISAID) database. With the help of Genome Detective Coronavirus Typing Tool, genomic sequences were aligned with the Wuhan seafood market pneumonia virus reference sequence and all the mutations were identified. Distribution of mutant variants was then compared between mildly and severely affected groups. Among the numerous mutations detected, 14408C>T and 23403A>G mutations resulting in RNA-dependent RNA polymerase (RdRp) P323L and spike protein D614G mutations, respectively, were found predominantly in severely affected group (>82%) compared with mildly affected group (<46%, p < 0.001). The 241C>T mutation in the non-coding region of the genome was also found predominantly in severely affected group (p < 0.001). The 3037C>T, a silent mutation, also appeared in relatively high frequency in severely affected group compared with mildly affected group, but the difference was not statistically significant (p = 0.06). We concluded that spike protein D614G and RdRp P323L mutations in SARS-CoV-2 are associated with severity of COVID-19. Further studies will be required to explore whether these mutations have any impact on the severity of disease.

• Genomics & Informatics
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• 제14권3호
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• pp.78-84
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• 2016

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NKTCL), is a malignant disorder of cytotoxic lymphocytes of NK or T cells. It is an aggressive neoplasm with a very poor prognosis. Although extranodal NKTCL reportedly has a strong association with Epstein-Barr virus, the molecular pathogenesis of NKTCL has been unexplored. The recent technological advancements in next-generation sequencing (NGS) have made DNA sequencing cost- and time-effective, with more reliable results. Using the Ion Proton Comprehensive Cancer Panel, we sequenced 409 cancer-related genes to identify somatic mutations in five NKTCL tissue samples. The sequencing analysis detected 25 mutations in 21 genes. Among them, KMT2D, a histone modification-related gene, was the most frequently mutated gene (four of the five cases). This result was consistent with recent NGS studies that have suggested KMT2D as a novel driver gene in NKTCL. Mutations were also found in ARID1A, a chromatin remodeling gene, and TP53, which also recurred in recent NGS studies. We also found mutations in 18 novel candidate genes, with molecular functions that were potentially implicated in cancer development. We suggest that these genes may result in multiple oncogenic events and may be used as potential bio-markers of NKTCL in the future.

• Experimental and Molecular Medicine
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• 제50권11호
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• pp.12.1-12.12
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• 2018

Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of ${\beta}$-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis. Therefore, we tested KYA1797K, a recently identified small molecule that degrades both ${\beta}$-catenin and Ras via $GSK3{\beta}$ activation, and its capability to suppress the cetuximab resistance of KRAS-mutated CRC cells. KYA1797K suppressed the growth of tumor xenografts induced by CRC cells as well as tumor organoids derived from CRC patients having both APC and KRAS mutations. Lowering the levels of both ${\beta}$-catenin and RAS as well as EGFR via targeting the $Wnt/{\beta}$-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the $Wnt/{\beta}$-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations.

• BMB Reports
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• 제47권6호
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• pp.299-310
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• 2014

Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells. Recent cancer genomics analyses have discovered a high frequency of somatic mutations in the genes encoding the core cohesin subunits as well as cohesin regulatory factors (e.g. NIPBL, PDS5B, ESPL1) in a select subset of human tumors including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia. Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations.

• Annals of Clinical Neurophysiology
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• 제11권2호
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• pp.59-63
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• 2009

Miyoshi myopathy (MM) is caused by the mutations of dysferlin gene (DYSF), which impairs the function of dysferlin protein causing muscle membrane dysfunction. We report a patient showing the MM phenotype who has a sister with LGMD 2B phenotype, along with the results of the immunohistochemical and molecular analyses of the DYSF gene. Immunohistochemical analysis noted negative immunoreactivity against dysferlin. Direct DNA sequencing of whole exons of DYSF gene revealed heterozygous nonsense mutations (c.610C>T + c.2494C>T). To our knowledge, this is the first reported MM case with this very combination of heterozygous mutations.

• BMB Reports
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• 제46권2호
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• pp.97-102
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• 2013

The use of various cancer cell lines can recapitulate known tumor-associated mutations and genetically define cancer subsets. This approach also enables comparative surveys of associations between cancer mutations and drug responses. Here, we analyzed the effects of ~40,000 compounds on cancer cell lines that showed diverse mutation-dependent sensitivity profiles. Over 1,000 compounds exhibited unique sensitivity on cell lines with specific mutational genotypes, and these compounds were clustered into six different classes of mutation-oriented sensitivity. The present analysis provides new insights into the relationship between somatic mutations and selectivity response of chemicals, and these results should have applications related to predicting and optimizing thera-peutic windows for anti-cancer agents.

• BMB Reports
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• 제57권1호
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• pp.19-29
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• 2024

Mitochondrial DNA (mtDNA), a multicopy genome found in mitochondria, is crucial for oxidative phosphorylation. Mutations in mtDNA can lead to severe mitochondrial dysfunction in tissues and organs with high energy demand. MtDNA mutations are closely associated with mitochondrial and age-related disease. To better understand the functional role of mtDNA and work toward developing therapeutics, it is essential to advance technology that is capable of manipulating the mitochondrial genome. This review discusses ongoing efforts in mitochondrial genome editing with mtDNA nucleases and base editors, including the tools, delivery strategies, and applications. Future advances in mitochondrial genome editing to address challenges regarding their efficiency and specificity can achieve the promise of therapeutic genome editing.

• 생명과학회지
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• 제34권7호
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• pp.520-530
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• 2024

종양 억제 유전자(TSG)는 세포 항상성을 유지하는 데 중요한 역할을 한다. 이러한 유전자의 기능이 상실되면 세포 가소성(cellular plasticity)이 유발되어 다양한 암, 특히 공격적인 성향을 가진 소세포 폐암(SCLC)이 발생할 수 있다. SCLC는 주로 후성학적 조절인자를 암호화하는 유전자에서 발생하는 다수의 기능 상실 돌연변이에 의해 유발된다. 이러한 돌연변이는 직접적으로 표적화하기 어렵기 때문에 치료제 개발이 어려운 상황이다. 그러나 이러한 돌연변이로 인한 분자적 변화를 이해하면 종양 치료 전략을 개발하는데 큰 도움이 될 수 있다. 우리는 SCLC의 이질적인 유전체 환경에도 불구하고 환자의 종양에서 발생하는 돌연변이의 영향이 악성 종양을 유발하는 몇 가지 중요한 경로로 수렴되고 있음을 확인하였다. 특히, 후성학적 변화는 전사 조절 장애를 초래하여 돌연변이 세포가 면역 회피 및 높은 전이 능력을 가진 매우 가소성이 높은 상태로 진입하게 한다. 본 논문에서는 반대 기능을 가진 후성학적 조절인자의 불균형이 면역 인식 마커의 상실로 이어져 종양 세포가 면역 체계로부터 효과적으로 회피하는 과정을 보여주는 연구들을 강조하였다. 또한 후성학적 조절인자가 신경내분비 세포 특성을 유지하는 역할과 비정상적인 전사 조절이 종양의 발달 및 진행 중 상피간엽이행(EMT)를 촉진하는 방법에 대해 서술하였다. 이 경로들은 별개의 것처럼 보이지만, 흔히 공통된 분자와 매개체를 공유하고 있음을 확인하였다. 빈번하게 변화하는 후성학적 조절인자 간의 연결을 이해하면 SCLC 및 유사한 돌연변이를 가진 다른 암의 발달과 진행의 분자적 메커니즘에 대한 귀중한 통찰력을 제공하여 예방 및 치료법 개발에 기여할 수 있을 것이다.

• Journal of Genetic Medicine
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• 제2권1호
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• pp.17-22
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• 1998

The Lesch-Nyhan syndrome which is caused by the deficiency of hypoxanthine guanine phosphoribosyltransferase is an X-linked recessive disorder characterized by hyperuricemia, choreoathetosis, mental retardation and compulsive self-injurious behavior. Clinical management of the patients with the Lesch-Nyhan syndrome is frustrating and requires burdensome medical treatment since it cripples the patient and shortens the life span by progression of neurological symptoms, but there are no cures or measures for relieving relentless natural course of the disease yet. Therefore, prenatal diagnosis of the affected fetus is important in genetic counselling for the family at high risk. In this study, four different mutations in the HPRT gene of four probands have been identified in four unrelated families; K215X, Q109X, nt.631 ${\Delta}A$, and nt.289 ${\Delta}GT$. Two mutations among them altered restriction enzyme sites; SpeI for Q109X and MaeI for nt.289 ${\Delta}GT$. Based on their molecular defects, prenatal diagnoses of 3 the fetuses were successfully made between ninth and eleventh week of gestation by polymerase chain reaction (PCR), restriction digestion and DNA sequencing using cDNA obtained from chorionic villus samples (CVS). We predicted the outcome of all fetuses prenatally. Among the three fetuses two were male and one was female according to the identification made by PCR amplification of the sex determining region of the Y chromosome(SRY) gene. Each carried a wild type allele for the corresponding mutant allele. They were also tested postnatally for the mutations to be unaffected.