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Transcriptomic Signature of Non-Alcoholic Fatty Liver Disease
( Murim Choi ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1
Nonalcoholic fatty liver disease (NAFLD) poses an impending clinical burden. Genome-wide association studies have revealed a limited contribution of genomic variants to the disease, requiring alternative but robust approaches to identify disease-associated variants and genes. We carried out a disease-specific expression quantitative trait loci (eQTL) screen to identify novel genetic factors that specifically act on NAFLD tissues on the basis of genotype. We recruited 125 Korean biopsy-proven NAFLD patients and healthy individuals without histological evidence of NAFLD and performed eQTL analysis. We then selected NAFLD-specific eQTLs that are active only under the diseased state. Among the 243 loci, AGXT2, encoding alanine-glyoxylate aminotransferase 2, displayed decreased expression in NAFLD patients homozygous for the non-reference allele of rs2291702, compared to no-NAFLD subjects with the same genotype. This change was replicated in an additional 165 individuals. Knockdown of AGXT2 in cell and mouse models exacerbated fibrosis, whereas overexpression ameliorated it. Reduced AGXT2 induced ER stress and cell death, eventually providing susceptibility to the disease in a genotype- dependent manner. Our overall approach will serve as an efficient tool for uncovering novel genetic factors that contribute to liver steatosis and fibrosis in patients with NAFLD.
Expression patterns of astrocyte elevated gene-1 (AEG-1) during development of the mouse embryo
Jeon, Hyun Yong,Choi, Murim,Howlett, Eric L.,Vozhilla, Nikollaq,Yoo, Byoung Kwon,Lloyd, Joyce A.,Sarkar, Devanand,Lee, Seok-Geun,Fisher, Paul B. Elsevier 2010 Gene expression patterns Vol.10 No.7
<P><B>Abstract</B></P><P>Expression of astrocyte elevated gene-1 (AEG-1) is elevated in multiple human cancers including brain tumors, neuroblastomas, melanomas, breast cancers, non-small cell lung cancers, liver cancers, prostate cancers, and esophageal cancers. This gene plays crucial roles in tumor cell growth, invasion, angiogenesis and progression to metastasis. In addition, over-expression of AEG-1 protects primary and transformed cells from apoptosis-inducing signals by activating PI3K-Akt signaling pathways. These results suggest that AEG-1 is intimately involved in tumorigenesis and may serve as a potential therapeutic target for various human cancers. However, the normal physiological functions of AEG-1 require clarification. We presently analyzed the expression pattern of AEG-1 during mouse development. AEG-1 was expressed in mid-to-hindbrain, fronto-nasal processes, limbs, and pharyngeal arches in the early developmental period from E8.5 to E9.5. In addition, at stages of E12.5–E18.5 AEG-1 was localized in the brain, and olfactory and skeletal systems suggesting a role in neurogenesis, as well as in skin, including hair follicles, and in the liver, which are organ sites in which AEG-1 has been implicated in tumor development and progression. AEG-1 co-localized with Ki-67, indicating a role in cell proliferation, as previously revealed in tumorigenesis. Taken together, these results suggest that AEG-1 may play a prominent role during normal mouse development in the context of cell proliferation as well as differentiation, and that temporal regulation of AEG-1 expression may be required during specific stages and in specific tissues during development.</P>
Goh, Gerald,Choi, Murim Korea Genome Organization 2012 Genomics & informatics Vol.10 No.4
The recent advent of next-generation sequencing technologies has dramatically changed the nature of biomedical research. Human genetics is no exception-it has never been easier to interrogate human patient genomes at the nucleotide level to identify disease-associated variants. To further facilitate the efficiency of this approach, whole exome sequencing (WES) was first developed in 2009. Over the past three years, multiple groups have demonstrated the power of WES through robust disease-associated variant discoveries across a diverse spectrum of human diseases. Here, we review the application of WES to different types of inherited human diseases and discuss analytical challenges and possible solutions, with the aim of providing a practical guide for the effective use of this technology.
The role of de novo variants in complex and rare diseases pathogenesis
Mahir Rahman,Woohyung Lee,Murim Choi 대한의학유전학회 2015 대한의학유전학회지 Vol.12 No.1
De novo variants (DNVs) can arise during parental germ cell formation, fertilization, and the processes of embryogenesis. It is estimated that each individual carries 60-100 such spontaneous variants in the genome, most of them benign. However, a number of recent studies suggested that DNVs contribute to the pathogenesis of a variety of human diseases. Applications of DNVs include aiding in clinical diagnosis and identifying disease-causing genetic factors in patients with atypical symptoms. Therefore, understanding the roles of DNVs in a trio, with healthy parents and an affected offspring, would be crucial in elucidating the genetic mechanism of disease pathogenesis in a personalized manner.
<i>ITGB6</i> loss-of-function mutations cause autosomal recessive amelogenesis imperfecta
Wang, Shih-Kai,Choi, Murim,Richardson, Amelia S.,Reid, Bryan M.,Lin, Brent P.,Wang, Susan J.,Kim, Jung-Wook,Simmer, James P.,Hu, Jan C.-C. Oxford University Press 2014 Human Molecular Genetics Vol.23 No.8
<P>Integrins are cell-surface adhesion receptors that bind to extracellular matrices (ECM) and mediate cell–ECM interactions. Some integrins are known to play critical roles in dental enamel formation. We recruited two Hispanic families with generalized hypoplastic amelogenesis imperfecta (AI). Analysis of whole-exome sequences identified three <I>integrin beta 6</I> (<I>ITGB6</I>) mutations responsible for their enamel malformations. The female proband of Family 1 was a compound heterozygote with an <I>ITGB6</I> transition mutation in Exon 4 (g.4545G > A c.427G > A p.Ala143Thr) and an <I>ITGB6</I> transversion mutation in Exon 6 (g.27415T > A c.825T > A p.His275Gln). The male proband of Family 2 was homozygous for an <I>ITGB6</I> transition mutation in Exon 11 (g.73664C > T c.1846C > T p.Arg616*) and hemizygous for a transition mutation in Exon 6 of <I>Nance–Horan Syndrome</I> (<I>NHS</I> Xp22.13; g.355444T > C c.1697T > C p.Met566Thr). These are the first disease-causing <I>ITGB6</I> mutations to be reported. Immunohistochemistry of mouse mandibular incisors localized ITGB6 to the distal membrane of differentiating ameloblasts and pre-ameloblasts, and then ITGB6 appeared to be internalized by secretory stage ameloblasts. ITGB6 expression was strongest in the maturation stage and its localization was associated with ameloblast modulation. Our findings demonstrate that early and late amelogenesis depend upon cell–matrix interactions. Our approach (from knockout mouse phenotype to human disease) demonstrates the power of mouse reverse genetics in mutational analysis of human genetic disorders and attests to the need for a careful dental phenotyping in large-scale knockout mouse projects.</P>
Ultra-rare Disease and Genomics-Driven Precision Medicine
Lee, Sangmoon,Choi, Murim Korea Genome Organization 2016 Genomics & informatics Vol.14 No.2
Since next-generation sequencing (NGS) technique was adopted into clinical practices, revolutionary advances in diagnosing rare genetic diseases have been achieved through translating genomic medicine into precision or personalized management. Indeed, several successful cases of molecular diagnosis and treatment with personalized or targeted therapies of rare genetic diseases have been reported. Still, there are several obstacles to be overcome for wider application of NGS-based precision medicine, including high sequencing cost, incomplete variant sensitivity and accuracy, practical complexities, and a shortage of available treatment options.