22q11.2 미세 결실 증후군 환아에서 내분비 기능 및 성장에 관한 연구

이종승,최진호,유한욱 대한소아내분비학회 2004 Annals of Pediatirc Endocrinology & Metabolism Vol.9 No.1

한국인 Fragile-X 증후군 환자의 분자 유전학적 진단

김경모,유한욱 울산대학교 의과대학 1994 울산의대학술지 Vol.3 No.2

Fragile-X syndrome (FXS) is the most common cause of inherited mental retardation. Until recently, the diagnosis of FXS has been made based on the cytogenetic expression of the fragile site at Xq27.3 (FRAXA) in the patients' cultured cells and on the results of linkage analysis with DNA markers surrounding the fragile X locus. The recent cloning of fragile-X gene(FMR-1) made it possible investigate the molecular defects in FMR-1 gene of individuals at risk. Vast majority of molecular defects of FXS has been known to be an abnormally amplified trinucleotide(cytosine guanine guanine) repeat. This study aims at establishing the molecular genetic diagnosis of FXS as well as correlating genotype-phenotype analyzing the increment of amplified CGG repeat number, clinical findings, and cytogenetic expression rate in two Korean families with FXS patients. The FXS patients are tested cytogenetically & molecular genetically. The fragile site at Xq27.3 was cytogenetically expressed in folate deficient medium by culturing lymphocytes for 4 days. Molecular diagnostic approaches utilize the genomic DNA Southern blot analysis using genomic probe FXA 241 (ONCOR) and radiolabelled PCR-denaturing polyacrylamide gelelcetrophoresis. Each patient expressed a FRAXA site in folate deficient medium with the expression rate of 38%, 16% respectively. The molecular genetic study showed that each patient had the CGG amplification 1.6kb, 0.7-0.8kb in the FMR-1 gene respectively. In addition, this study clarified the carrier status of each family members. In conclusion, molecular genetic studies employed in this study can be utilized for a confimatory diagnostic purpose in FXS patients.

Molecular characterization and prenatal molecular evaluation of three fetuses in four unrelated Korean families with Lesch-Nyhan syndrome

Han-Wook Yoo,Gu-Hwan Kim 대한의학유전학회 1998 대한의학유전학회지 Vol.2 No.1

The Lesch-Nyhan syndrome which is caused by the deficiency of hypoxanthine guanine phosphoribosyl-transferase 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 ΔA, and nt.289 ΔGT. Two mutations among them altered restriction enzyme sites; Spel for Q109X and Mael for nt.289 ΔGT. 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.

Clinical Features, Response to Treatment, Prognosis, and Molecular Characterization in Korean Patients with Inherited Urea Cycle Defects

Yoo, Han-Wook,Kim, Gu-Hwan,Seo, Eul-Ju The Korean Society of Inherited Metabolic Disease 2002 대한유전성대사질환학회지 Vol.2 No.1

The urea cycle, consisting of a series of six enzymatic reactions, plays key roles to prevent the accumulation of toxic nitrogenous compound and synthesize arginine de novo. Five well characterized diseases have been described, resulting from an enzymatic defect in the biosynthesis of one of the normally expressed enzyme. This presentation will focus on two representative diseases; ornithine transcarbamylase(OTC) deficiency and citrullinemia(argininosuccinate synthetase deficiency). OTC deficiency is one of the most common inborn error of urea cycle, which is inherited in X-linked manner. We identified 17 different mutations in 20 unrelated Korean patients with OTC deficiency; L9X, R26P, R26X, T44I, R92X, G100R, R141Q, G195R, M205T, H214Y, D249G, R277W, F281S, 853 del C, R320X, V323M and 10 bp del at nt. 796-805. These mutations occur at well conserved nucleotide sequences across species or CpG hot spot. The L9X and R26X lead to the disruption of leader sequences, required for directing mitochondrial localization of the OTC precursor. Their phenotypes are severe, and neonatal onset. The G100R, R277W and V323M mutations were uniquely identified in patients with late onset OTC deficiency. The other genotypes are associated with neonatal onset. Out of 20 patients with OTC deficiency, only 6 patients are alive; two were liver transplanted, and normal in growth and development at 2, 4 years after transplantation respectively. Citrullinemia is an autosomal recessive disease, caused by the mutations in the argininosuccinate synthetase(ASS) gene. We identified in 3 major mutations in 11 unrelated Korean patients with citrullinemia; G324S, $IVS6^{-2}$ A to G, and 67 bp ins at nt 1125-1126. Among these, the 67 base pair insertion mutation is novel. The allele frequency of each mutation is; G324S(45%), IVS6-2 A to G(32%), and 67 base pair insertion(14%). All patients are diagnosed at neonatal or infantile age. Interestingly, two patients presented with stroke like episode. Out of 11 patients, 5 patients died. Among 6 patients alive, one patient was successfully liver transplanted.

Inborn Errors of Mitochondrial Fatty Acid Oxidation: Overview from a Clinical Perspective

Han-Wook Yoo 한국지질동맥경화학회 2021 지질·동맥경화학회지 Vol.10 No.1

Mitochondrial fatty acid β-oxidation (mFAO), which is the major pathway for the degradation of fatty acids and is critical for maintaining energy homeostasis in the human body, consists of carnitine transport, the carnitine shuttle, and fatty acid β-oxidation. Inherited metabolic defects of mFAO result in more than 15 distinct mFAO disorders (mFAODs) with varying clinical manifestations. The common elements of the clinical presentation of mFAODs are hypoketotic hypoglycemia, (cardio)myopathy, arrhythmia, and rhabdomyolysis, indicating the importance of FAO during fasting or stressful situations. The management of all mFAODs includes avoidance of fasting, aggressive treatment during illness, and supplementation of carnitine or appropriate nutritional support, if necessary. Through the introduction of newborn screening using tandem mass spectrometry, early identification of mFAODs became feasible, leading to an early initiation of treatment with improved outcomes. However, many unmet needs remain with regard to the long-term management of patients with mFAODs.

Genetic testing in clinical pediatric practice

Yoo, Han Wook The Korean Pediatric Society 2010 Clinical and Experimental Pediatrics (CEP) Vol.53 No.3

Completion of the human genome project has allowed a deeper understanding of molecular pathophysiology and has provided invaluable genomic information for the diagnosis of genetic disorders. Advent of new technologies has lead to an explosion in genetic testing. However, this overwhelming stream of genetic information often misleads physicians and patients into a misguided faith in the power of genetic testing. Moreover, genetic testing raises a number of ethical, legal, and social issues. Diagnostic genetic tests can be divided into three primary but overlapping categories: cytogenetic studies (including routine karyotyping, high-resolution karyotyping, and fluorescent in situ hybridization studies), biochemical tests, and DNA-based diagnostic tests. DNA-based testing has grown rapidly over the past decade and includes preandpostnatal testing for the diagnosis of genetic diseases, testing for carriers of genetic diseases, genetic testing for susceptibility to common non-genetic diseases, and screening for common genetic diseases in a particular population. Theoretically, once a gene's structure, function, and association with a disease are well established, the clinical application of genetic testing should be feasible. However, for routine applications in a clinical setting, such tests must satisfy a number of criteria. These criteria include an acceptable degree of clinical and analytical validity, support of a quality assurance program, possibility of modifying the course of the diagnosed disease with treatment, inclusion of pre-and postnatal genetic counseling, and determination of whether the proposed test satisfies cost-benefit criteria and should replace or complement traditional tests. In the near future, the application of genetic testing to common diseases is expected to expand and will likely be extended to include individual pharmacogenetic assessments.

A Korean patient with Fanconi-Bickel Syndrome Presenting with Transient Neonatal Diabetes Mellitus and Galactosemia : Identification of a Novel Mutation in the GLUT2 Gene

Yoo, Han-Wook,Seo, Eul-Ju,Kim, Gu-Hwan The Korean Society of Inherited Metabolic Disease 2001 대한유전성대사질환학회지 Vol.1 No.1

Fanconi-Bickel Syndrome (FBS) is a rare autosomal recessive disorder of carbohydrate metabolism recently demonstrated to be caused by mutations in the GLUT 2 gene for the glucose transporter protein 2 expressed in liver, pancreas, intestine, and kidney. This disease is characterized by hepatorenal glycogen accumulation, both fasting hypoglycemia as well as postprandial hyperglycemia and hyperglactosemia, and generalized proximal renal tubular dysfunctions. We report the first Korean patient with FBS diagnosed based on clinical manifestations and identification of a novel mutation in the GLUT 2 gene. She was initially diagnosed having a neonatal diabetes mellitus due to hyperglycemia and glycosuria at 3 days after birth. In addition, newborn screening for galactosemia revealed hypergalactosemia. Thereafter, she has been managed with lactose free milk, insulin therapy. However, she failed to grow and her liver has been progressively enlarging. Her liver functions were progressively deteriorated with increased prothrombin time. Liver biopsy done at age 9 months indicated micronodular cirrhosis with marked fatty changes. She succubmed to hepatic failiure with pneumonia at 10 months of age. Laboratory tests indicated she had generalized proximal renal tubular dysfuctions; renal tubular acidosis, hypophosphatemic rickets, and generalized aminoaciduria. Given aforementioned findings, the diagnosis of FBS was appreciated at age of 2 months. The DNA sequencing analysis of the GLUT 2 gene using her genomic DNA showed a novel mutation at 5th codon; Lysine5 Stop (K5X).

Enhanced SMAD1 Signaling Contributes to Impairments of Early Development in CFC-iPSCs.

Han, Kyu-Min,Kim, Seung-Kyoon,Kim, Dongkyu,Choi, Jung-Yun,Im, Ilkyun,Hwang, Kyu-Seok,Kim, Cheol-Hee,Lee, Beom Hee,Yoo, Han-Wook,Han, Yong-Mahn AlphaMed Press 2015 Stem Cells Vol.33 No.5

<P>Cardio-facio-cutaneous (CFC) syndrome is a developmental disorder caused by constitutively active ERK signaling manifesting mainly from BRAF mutations. Little is known about the role of elevated ERK signaling in CFC syndrome during early development. Here, we show that both SMAD1 and ERK signaling pathways may contribute to the developmental defects in CFC syndrome. Induced pluripotent stem cells (iPSCs) derived from dermal fibroblasts of a CFC syndrome patient (CFC-iPSCs) revealed early developmental defects in embryoid body (EB) development, β-catenin localization, and neuronal differentiation. Both SMAD1 and ERK signalings were significantly activated in CFC-iPSCs during EB formation. Most of the β-catenin was dissociated from the membrane and preferentially localized into the nucleus in CFC-EBs. Furthermore, activation of SMAD1 signaling recapitulated early developmental defects in wild-type iPSCs. Intriguingly, inhibition of SMAD1 signaling in CFC-iPSCs rescued aberrant EB morphology, impaired neuronal differentiation, and altered β-catenin localization. These results suggest that SMAD1 signaling may be a key pathway contributing the pathogenesis of CFC syndrome during early development.</P>

Performance Evaluation of Fiber-Optic Dosimeter According to Current-Time Product of Digital Radiography System

Yoo, Wook Jae,Jeon, Da Yeong,Seo, Jeong Ki,Shin, Sang Hun,Han, Ki Tek,Hong, Seung Han,Kim, Seon Guen,Sim, Hyeok In,Cho, Seung Hyun,Lee, Bong Soo Trans Tech Publications, Ltd. 2013 Advanced materials research Vol.718 No.-

<P>A fiber-optic dosimeter was developed using a plastic scintillating fiber, a plastic optical fiber, and a photomultiplier tube for measuring entrance surface dose over the low-energy range which is interested in diagnostic radiology. To evaluate the fabricated fiber-optic dosimeter, the scintillating light signals were measured by changing the current-time product whose values were determined by tube current and irradiation time of a digital radiography system. In conclusion, the trend of scintillating light signals of the fiber-optic dosimeter was similar with that of the entrance surface doses of a commercially available semiconductor dosimeter according to the current-time product.</P>

Molecular characterization and prenatal molecular evaluation of three fetuses in four unrelated Korean families with Lesch-Nyhan syndrome

Yoo, Han-Wook,Kim, Gu-Hwan Korean Society of Medical Genetics 1998 대한의학유전학회지 Vol.2 No.1

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.