Novel Heterozygous Mutations of NR5A1 and Their Functional Characteristics in Patients with 46,XY Disorders of Sex Development without Adrenal Insufficiency.

BACKGROUND/AIMS: Heterozygous mutations of NR5A1, which encodes steroidogenic factor 1 (SF1), were identified in patients with 46,XY disorders of sex development (DSD) with normal adrenal function. This study was aimed to identify and functionally characterize mutations of NR5A1 in patients with 46,XY DSD. METHODS: This study included 51 patients from 49 unrelated families with 46,XY DSD. Genomic DNA was extracted from peripheral blood leukocytes, and direct sequencing of all coding exons and their flanking introns of NR5A1 was performed. Transient transfections and dual-luciferase® reporter assays were performed to evaluate the effect of NR5A1 variants on transcriptional activity. RESULTS: Four of 49 patients (8.2%) harbored a novel heterozygous sequence variant of NR5A1: c.80G>C (p.G26A), c.847T>C (p.C283R), c.1151del (p.L384Rfs*7), and c.1333G>T (p.E445*). They presented with female external genitalia with clitoromegaly in infancy or childhood, or primary amenorrhea in adolescence. In vitro functional studies of SF1 activity determined that each variant, except p.E445*, led to a reduced expression of downstream target genes and disturbed the regulation of gonadal development. CONCLUSIONS: Loss-of-function mutations of NR5A1 are a relatively common cause of 46,XY DSD. Therefore, genetic defects of NR5A1 should be considered as an etiology in subjects with 46,XY DSD without adrenal insufficiency.

Identification and Functional Characterization of Two Novel Nonsense Mutations in the ß-Subunit of INSR That Cause Severe Insulin Resistance Syndrome.

BACKGROUND/AIMS: Donohue syndrome is an extremely rare autosomal recessive disorder caused by mutations in INSR. This study describes the clinical course of a patient with Donohue syndrome, and we also evaluated the molecular and functional characteristics of 2 novel INSR mutations. METHODS: Our patient was a male newborn with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, and high serum insulin levels, all of which are characteristic of Donohue syndrome. INSR mutation analysis was performed, and Western blot analysis was used to verify the effects of the novel mutations on INSR protein expression. RESULTS: Direct INSR sequencing identified the following 2 novel compound heterozygous mutations in the ß-subunit of INSR: p.Arg1066* and p.Gln1232*. Western blot analysis of skin fibroblasts revealed a comparable expression of the α-subunit of INSR in mutant and control samples, but reduced levels of mature INSR ß-subunit protein were found in mutant INSR-expressing cells in comparison to the controls. CONCLUSIONS: This study describes the clinical course of a male patient with Donohue syndrome and the molecular characteristics of 2 novel compound heterozygous mutations in INSR. These novel nonsense mutations are associated with reduced expression of the mature INSR ß-subunit, which was most likely due to impaired proreceptor processing.

Clinical outcomes and the mutation spectrum of the OTC gene in patients with ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) deficiency is an X-linked inborn error of the urea cycle that leads to the accumulation of ammonia, resulting in neurological deficits. This study was performed to describe the clinical outcomes, biochemical features and molecular spectra of patients with OTC deficiency. A total of 49 patients from 47 unrelated Korean pedigrees were included who were diagnosed with OTC deficiency based on biochemical findings and molecular analyses. Patient clinical features,biochemical findings and molecular data were analyzed retrospectively. Males with neonatal-onset phenotype presented with seizure or altered mentality (n=20). Biochemical findings showed high blood ammonia (1132.5±851.6 µmol l (− 1)) and urineorotic acid (1840.7±1731.3 mmol mol(− 1) Cr) levels. There were also five males with late-onset disease who presented with vomiting, irritability and seizure at age 8.2±9.4 years old (range, 0.6­20 years). Symptomatic females presented with vomiting,seizure, and altered mentality at age 3.5±3.5 years (range, 0.2­12.8 years; n=24). More males with the late-onset form and symptomatic females displayed mild hyperammonemia and orotic aciduria compared with those showing a neonatal phenotype (P<0.05). Molecular analysis identified 37 different mutations (22 missense, 5 large deletions, 4 small deletions, 1 insertion,3 nonsense and 2 splice sites) from all 49 patients; the mutations were dispersed throughout all coding exons. In Korean patients with OTC deficiency, mutations in OTC are genetically heterogeneous. Male patients with the neonatal-onset phenotype showed poor outcomes because of severe hyperammonemia. Early diagnosis and interventions for hyperammonemia can provide more favorable prognosis.

Current status of production and market of human vaccine products in Korea.

PURPOSE: The goal of this study was to build basic information related to the production and market of human vaccine products in Korea, which can be an important indicator to provide basic data in practical use. MATERIALS AND METHODS: Statistical data were obtained from the Bank of Korea, Korea Health Industry Development Institute, Korea Pharmaceutical Traders Association, and Korea Pharmaceutical Manufacturers Association. RESULTS: Vaccines are the 10th ranked drugs in the classification of whole complete preparated drugs. The production output of vaccines in Korea was 392.2 billion KRW in 2011, comprising 2.83% of complete preparated drug production output (13 trillion 880.8 billion KRW) and 2.54% of medical-pharmaceutical product output (15 trillion 440.3 billion KRW). The market scale of vaccines in Korea was 710 billion KRW in 2011, with an annual average growth rate of 11% in the past 6 years, comprising 2% of vaccine market in the world. There was also a significant increase in essential vaccines and other preventive vaccines in a global scale. CONCLUSION: Vaccines have the potential of becoming an emerging attractive industry. Based on the current analysis about the production of vaccine products and market scale, further development of the vaccine industry is expected in Korea.

Current status of registry of vaccine clinical trials conducted by Korean investigators in ClinicalTrials.gov, database of US National Institutes of Health.

PURPOSE: PubMed is not only includes international medical journals but also has a registration site for the ongoing clinical trials, such as ClinicalTrials.gov, under the supervision of US National Institutes of Health. We analyzed current status of vaccine clinical trials conducted by Korean investigators in database of ClinicalTrial.gov. MATERIALS AND METHODS: As of October 2012, there are total of 72 trials found on registry of vaccine clinical trials conducted by Korean investigators in database of ClinicalTrial.gov. These trials were analyzed and classified by conditions of vaccine clinical trials, biologicals or drugs used in vaccine clinical trials, status of proceeding research, and list of sponsor and collaborators. RESULTS: Total 72 trials of vaccine clinical trials conducted by Korean investigators are classified by groups of infection (64 trials), cancer (4 trials), and others (4 trials). Infections group shown are as follows: poliomyelitis, pertussis, diphtheria, tetanus, and Haemophilus influenzae type b (10), influenza (9), human papillomavirus infection (8), pneumococcal vaccine (6), herpes zoster (4), smallpox (4), hepatitis B (4), etc. One trial of each in lung cancer, breast cancer, prostate cancer, and colorectal cancer are shown in cancer group. One trial of each in Crohn's disease, ulcerative colitis, renal failure, and rheumatoid arthritis are shown in other group. CONCLUSION: Vaccine clinical trials conducted by Korean investigators in ClinicalTrial.gov reflects the current status of Korean research on vaccine clinical trials at the international level and can indicate research progress. It is hoped that this aids the development of future vaccine clinical trials in Korea.