Speech and language are uniquely human-specific traits, which contributed to humans becoming the predominant species on earth. Disruptions in the human speech and language function may result in diverse disorders. These include stuttering, aphasia, articulation disorder, spasmodic dysphonia, verbal dyspraxia, dyslexia and specific language impairment. Among these disorders, stuttering is the most common speech disorder characterized by disruptions in the normal flow of speech. Twin, adoption, and family studies have suggested that genetic factors are involved in susceptibility to stuttering. For several decades, multiple genetic studies including linkage analysis were performed to connect causative gene to stuttering, and several genetic studies have revealed the association of specific gene mutation with stuttering. One notable genetic discovery came from the genetic studies in the consanguineous Pakistani families. These studies suggested that mutations in the lysosomal enzyme-targeting pathway genes (GNPTAB, GNPTG and NAPGA) are associated with non-syndromic persistent stuttering. Although these studies have revealed some clues in understanding the genetic causes of stuttering, only a small fraction of patients are affected by these genes. In this study, we summarize recent advances and future challenges in an effort to understand genetic causes underlying stuttering.
Aphasia ; Apraxias ; Articulation Disorders ; Dyslexia ; Dysphonia ; Genetic Linkage ; Humans ; Lysosomes ; Stuttering*

Speech and language functions are highly cognitive and human-specific features. The underlying causes of normal speech and language function are believed to reside in the human brain. Developmental persistent stuttering, a speech and language disorder, has been regarded as the most challenging disorder in determining genetic causes because of the high percentage of spontaneous recovery in stutters. This mysterious characteristic hinders speech pathologists from discriminating recovered stutters from completely normal individuals. Over the last several decades, several genetic approaches have been used to identify the genetic causes of stuttering, and remarkable progress has been made in genome-wide linkage analysis followed by gene sequencing. So far, four genes, namely GNPTAB, GNPTG, NAGPA, and AP4E1, are known to cause stuttering. Furthermore, thegeneration of mouse models of stuttering and morphometry analysis has created new ways for researchers to identify brain regions that participate in human speech function and to understand the neuropathology of stuttering. In this review, we aimed to investigate previous progress, challenges, and future perspectives in understanding the genetics and neuropathology underlying persistent developmental stuttering.

Uncovering enzyme (UCE), encoded by the human NAGPA, is a trans-Golgi enzyme that adds the mannose-6-phosphate recognition tag on lysosomal enzymes destined for the lysosome. Mutations in NAGPA are known to cause stuttering, a common speech disorder with unknown etiology. The human NAGPA gene is transcribed into two different forms, probably due to alternative splicing. One of them, known as a brain isoform, is lacking exon 8 (102-bp). We performed quantitative real-time PCR for the NAGPA brain and non-brain isoforms in a cDNA panel originating from 16 human tissues and 24 sub-brain regions. According to our findings, the relative quantity of the NAGPA brain isoform in the brain was 4.7 times more than that in the control cDNA, a pooled mixture of equal amounts of cDNAs from the 16 different tissues. Further analysis using the cDNA panel originating from 24 different sub-brain regions revealed that the cerebral cortex contained the largest amount of NAGPA brain isoform. Relative quantity in the cerebral cortex was 8.6 times more than that in the control cDNA (P=0.00004). The lowest quantity of this isoform was detected in cDNA from the pituitary gland. In conclusion, findings of the current study suggest that the cerebral cortex, expressing the highest quantity of the NAGPA brain isoform, might be the region associated with speech function.
Alternative Splicing ; Brain ; Cerebral Cortex ; DNA, Complementary* ; Exons ; Humans* ; Lysosomes ; Mannosephosphates ; Phosphoric Diester Hydrolases ; Pituitary Gland ; Protein Isoforms* ; Real-Time Polymerase Chain Reaction ; Stuttering

Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with both genetic and environmental factors. The DRB1 gene at the human leukocyte antigen (HLA) locus of chromosome 6p21.3 was the first genetic factor associated with RA to be identified in the 1980s; however, identification of causative genes other than those at the HLA locus has been challenging for geneticists because of the strong linkage disequilibrium in this locus and the non-Mendelian inheritance pattern of RA. Recent advances in high-throughput single nucleotide polymorphism genotyping technologies and bioinformatic analysis tools have facilitated the identification of positive associations of hundreds of genes with RA using family-based linkage analyses and genome wide association studies. Some of the RA associated genes at non-HLA loci are as follows: PADI4, PTPN22, STAT4, and TNFAIP3. In this paper, we describe the pathological mechanisms mediated by these genes. In addition, we review results of previous genetic studies of RA and future challenges in connecting the dots of missing heritability in the post-genome-wide association study era.
Arthritis, Rheumatoid* ; Genetics ; Genome-Wide Association Study ; Humans ; Inheritance Patterns ; Leukocytes ; Linkage Disequilibrium ; Polymorphism, Single Nucleotide

Speech and language are uniquely human-specific traits that have contributed to humans becoming the predominant species on earth from an evolutionary perspective. Disruptions in human speech and language function may result in diverse disorders, including stuttering, aphasia, articulation disorder, spasmodic dysphonia, verbal dyspraxia, dyslexia, and specific language impairment (SLI). These disorders often cluster within a family, and this clustering strongly supports the hypothesis that genes are involved in human speech and language functions. For several decades, multiple genetic studies, including linkage analysis and genomewide association studies, were performed in an effort to link a causative gene to each of these disorders, and several genetic studies revealed associations between mutations in specific genes and disorders such as stuttering, verbal dyspraxia, and SLI. One notable genetic discovery came from studies on stuttering in consanguineous Pakistani families; these studies suggested that mutations in lysosomal enzyme-targeting pathway genes (GNPTAB, GNPTG, and NAPGA) are associated with non-syndromic persistent stuttering. Another successful study identified FOXP2 in a Caucasian family affected by verbal dyspraxia. Furthermore, an abnormal ultrasonic vocalization pattern (USV) was observed in knock-in (KI) and humanized mouse models carrying mutations in the FOXP2 gene. Although studies have increased our understanding of the genetic causes of speech and language disorders, these genes can only explain a small fraction of all disorders in patients. In this paper, we summarize recent advances and future challenges in an effort to reveal the genetic causes of speech and language disorders in animal models.
Animals ; Aphasia ; Apraxias ; Articulation Disorders ; Dyslexia ; Dysphonia ; Humans ; Language Disorders* ; Mice ; Models, Animal ; Stuttering ; Ultrasonics

No abstract available.
Korea* ; Lung Neoplasms* ; Lung* ; Radon*

Acknowledgements section was missing. The publisher apologises for these errors.

BACKGROUND: To assess the association between ambient particulate matter and cardiovascular death in seven cities in the Republic of Korea during the period of 2002-2008. METHODS: A time-stratified case-crossover design was used to examine association between particulate matter and deaths from cardiovascular or cerebrovascular disease; hypertensive disease 12,821, ischemic heart disease 39,577, cardiac arrhythmia 1,627, cerebrovascular disease 88,047. Mortality data was obtained from National Statistical Office, and hourly mean concentrations of particulate matter < or = 10 microm in aerodynamic diameter and meteorological data were obtained from the Ministry of Environment. The percent increase in the risk of death associated with an interquartile range increase in particulate matter was determined by conditional logistic regression analysis after adjusting for national holidays and meteorological factors. RESULTS: The largest association was a 0.8% increase (95% confidence interval [CI], 0.1-1.6) in death risk related to an interquartile range increase in particulate matter < or = 10 microm (average of 0 to 2 days prior to the day of death). Classified as the cause of death, the association was a 1.2% increase (95% CI, 0.2-2.2) in death from cerebrovascular disease related to an interquartile range increase in particulate matter < or = 10 microm. But others were statistically not significant. After stratification of death cases by year of death, statistically significant associations were a 2.3% increase (95% CI, 0.1-4.4) in death risk from ischemic heart disease in 2002-2004 and 2.0% increase in death from cerebrovascular disease (95% CI, 0.3-3.8) in 2006-2008. CONCLUSIONS: Our results suggest that ambient air pollution increases the risk of deaths from cardiovascular and cerebrovascular disease in the Republic of Korea.
Air Pollution ; Arrhythmias, Cardiac ; Cardiovascular Diseases ; Cause of Death ; Cerebrovascular Disorders ; Cross-Over Studies ; Holidays ; Logistic Models ; Myocardial Ischemia ; Particulate Matter ; Republic of Korea

PURPOSE: The association between liver enzymes and death from external causes has not been examined. We investigated the association between serum aminotransferase levels and external-cause mortality in a large prospective cohort study. MATERIALS AND METHODS: A total of 142322 subjects of 35-59 years of age who completed baseline examinations in 1990 and 1992 were enrolled. Mortalities were identified using death certificates. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were categorized into quintiles. Sub-distribution hazards ratios and 95% confidence intervals (CIs) were estimated using a competing risks regression model in which deaths from other causes were treated as competing risks. RESULTS: Of 8808 deaths, 1111 (12.6%) were due to external causes. Injury accounted for 256 deaths, and suicide accounted for 255. After adjusting for covariates, elevated ALT and AST were significantly associated with an increased risk of all external-cause mortalities, as well as suicide and injury. Sub-distribution hazards ratios (95% CIs) of the highest versus the lowest quintiles of serum ALT and AST were, respectively, 1.57 (1.26-1.95) and 1.45 (1.20-1.76) for all external causes, 2.73 (1.68-4.46) and 1.75 (1.15-2.66) for suicide, and 1.79 (1.10-2.90) and 1.85 (1.21-2.82) for injury. The risk of external-cause mortality was also significantly higher in the fourth quintile of ALT (21.6-27.5 IU/L) than in its first quintile. CONCLUSION: Elevated aminotransferase levels, even within the normal range, were significantly associated with increased risk of all external-cause mortalities, including suicide, and injury.
Adult ; Alanine Transaminase/*blood/metabolism ; Aspartate Aminotransferases/*blood/metabolism ; Female ; Humans ; Male ; Middle Aged ; *Mortality ; *Population Surveillance ; Proportional Hazards Models ; Prospective Studies ; Republic of Korea/epidemiology ; Risk

PURPOSE: Exposure to indoor radon is associated with lung cancer. This study aimed to estimate the number of lung cancer deaths attributable to indoor radon exposure, its burden of disease, and the effects of radon mitigation in Korea in 2010. MATERIALS AND METHODS: Lung cancer deaths due to indoor radon exposure were estimated using exposure-response relations reported in previous studies. Years of life lost (YLLs) were calculated to quantify disease burden in relation to premature deaths. Mitigation effects were examined under scenarios in which all homes with indoor radon concentrations above a specified level were remediated below the level. RESULTS: The estimated number of lung cancer deaths attributable to indoor radon exposure ranged from 1946 to 3863, accounting for 12.5–24.7% of 15623 total lung cancer deaths in 2010. YLLs due to premature deaths were estimated at 43140–101855 years (90–212 years per 100000 population). If all homes with radon levels above 148 Bq/m3 are effectively remediated, 502–732 lung cancer deaths and 10972–18479 YLLs could be prevented. CONCLUSION: These findings suggest that indoor radon exposure contributes considerably to lung cancer, and that reducing indoor radon concentration would be helpful for decreasing the disease burden from lung cancer deaths.
Korea ; Lung Neoplasms* ; Lung* ; Mortality, Premature ; Radon*