Recessive Inheritance of Congenital Hydrocephalus With Other Structural Brain Abnormalities Caused by Compound Heterozygous Mutations in ATP1A3

Background: ATP1A3 encodes the α3 subunit of the Na+/K+ ATPase, a fundamental ion-transporting enzyme. Primarily expressed in neurons, ATP1A3 is mutated in several autosomal dominant neurological diseases. To our knowledge, damaging recessive genotypes in ATP1A3 have never been associated with any human disease. Atp1a3 deficiency in zebrafish results in hydrocephalus; however, no known association exists between ATP1A3 and human congenital hydrocephalus (CH). / Methods: We utilized whole-exome sequencing (WES), bioinformatics, and computational modeling to identify and characterize novel ATP1A3 mutations in a patient with CH. We performed immunohistochemical studies using mouse embryonic brain tissues to characterize Atp1a3 expression during brain development. / Results: We identified two germline mutations in ATP1A3 (p. Arg19Cys and p.Arg463Cys), each of which was inherited from one of the patient’s unaffected parents, in a single patient with severe obstructive CH due to aqueductal stenosis, along with open schizencephaly, type 1 Chiari malformation, and dysgenesis of the corpus callosum. Both mutations are predicted to be highly deleterious and impair protein stability. Immunohistochemical studies demonstrate robust Atp1a3 expression in neural stem cells (NSCs), differentiated neurons, and choroid plexus of the mouse embryonic brain. / Conclusion: These data provide the first evidence of a recessive human phenotype associated with mutations in ATP1A3, and implicate impaired Na+/K+ ATPase function in the pathogenesis of CH

Rare pathogenic variants in WNK3 cause X-linked intellectual disability

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordData availability: All data are available upon request. The sequence variants in WNK3 (NM_004656.3) reported in the paper have been deposited in ClinVar database. Their respective accession numbers (SCV002107163 to SCV002107168) are indicated in Tables 1 and S1.Purpose WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. Method We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). Results We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. Conclusion Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.Estonian Research CouncilNational Natural Science Foundation of ChinaRoyal SocietySouth Carolina Department of Disabilities and Special Needs (SCDDSN)National Institute of Neurological Disorders and Stroke (NINDS

Socioeconomic inequalities in catastrophic health expenditure and impoverishment associated with non-communicable diseases in urban Hanoi, Vietnam

Background: The catastrophic health expenditure and impoverishment indices offer guidance for developing appropriate health policies and intervention programs to decrease financial inequity. This study assesses socioeconomic inequalities in catastrophic health expenditure and impoverishment in relation to self-reported non-communicable diseases (NCD) in urban Hanoi, Vietnam. Methods: A cross-sectional survey was conducted from February to March 2013 in Hanoi, the capital city of Vietnam. We estimated catastrophic health expenditure and impoverishment using information from 492 slum household and 528 non-slum households. We calculated concentration indexes to assess socioeconomic inequalities in catastrophic health expenditure and impoverishment. Factors associated with catastrophic health expenditure and impoverishment were modelled using logistic regression analysis. Results: The poor households in both slum and non-slum areas were at higher risk of experiencing catastrophic health expenditure, while only the poor households in slum areas were at higher risk of impoverishment because of healthcare spending. Households with at least one member reporting an NCD were significantly more likely to face catastrophic health expenditure (odds ratio [OR] = 2.4; 95 % confidence interval [CI], 1.8-4.0) and impoverishment (OR = 2.3; 95 % CI, 1.1-6.3) compared to households without NCDs. In addition, households in slum areas, with people age 60 years and above, and belonging to the poorest socioeconomic group were significantly associated with increased catastrophic health expenditure, while only households that lived in slum areas, and belonging to the poor or poorest socioeconomic groups were significantly associated with increased impoverishment because of healthcare spending. Conclusion: Financial interventions to prevent catastrophic health expenditure and impoverishment should target poor households, especially those with family members suffering from NCDs, with older members and those located in slum areas in Hanoi Vietnam. Potential interventions derived from this study include targeting and monitoring of health insurance enrolment, and developing a specialized NCD service package for Vietnam's social health insurance program

Identification of genotype and phenotype of antimicrobial resistance of Escherichia coli isolates from pigs in southern Vietnam

Escherichia coli is a primary reservoir of antimicrobial resistance, known chiefly for the container of AMR-encoding genes (ARGs), and poses potential risks to human and animal health. This study investigated AMR phenotypes and ARGs in 90 E. coli isolates from different pig groups in 10 farms in southern Vietnam. The minimum inhibitory concentration (MIC) of 19 common antimicrobial agents was determined, and polymerase chain reaction (PCR) was used to investigate seven ARGs (blaTEM, aadA1, strA, dfrA12, sul3, cmlA and tetA). Cohen’s kappa statistic (κ) was applied to assess the concordance between phenotypic and genotypic profiles. A total of 81.1% of E. coli isolates were multi-drug resistant (MDR). The amphenicol class accounted for the highest resistance (100% isolates), followed by the tetracycline class (97.8%), the quinolones and penicillin classes (85.6% each), sulfonamides (67.8%) and aminoglycosides (63.3%). A greater proportion of isolates from weaner pigs showed resistance to multi-antibiotics (43.0%), followed by growers (39.5%) and finishers (36.3%), although the difference was not significant (P>0.05). The prevalence of ARGs was greatly variable and was highest for aadA1 (98.9%), cmlA (98.9%), blaTEM (97.8%), dfrA12 (97.8%), tetA (97.8%), sul3 (97.8%) and strA (83.3%). No significant correlation between ARGs and phenotypic resistance was identified. The results indicate a great diversity of genotypic and phenotypic AMR profiles in pig E. coli isolates. The lack of correlation might be a reflection of additional genes encoding the observed genotypic profiles or the presence of non-plasmid mediated resistance in many cases

High levels of contamination and antimicrobial-resistant non-typhoidal Salmonella serovars on pig and poultry farms in the Mekong Delta of Vietnam.

We investigated the prevalence, diversity, and antimicrobial resistance (AMR) profiles of non-typhoidal Salmonella (NTS) and associated risk factors on 341 pig, chicken, and duck farms in Dong Thap province (Mekong Delta, Vietnam). Sampling was stratified by species, district (four categories), and farm size (three categories). Pooled faeces, collected using boot swabs, were tested using ISO 6575: 2002 (Annex D). Isolates were serogrouped; group B isolates were tested by polymerase chain reaction to detect S. Typhimurium and (monophasic) serovar 4,[5],12:i:- variants. The farm-level adjusted NTS prevalence was 64·7%, 94·3% and 91·3% for chicken, duck and pig farms, respectively. Factors independently associated with NTS were duck farms [odds ratio (OR) 21·2], farm with >50 pigs (OR 11·9), pig farm with 5-50 pigs (OR 4·88) (vs. chickens), and frequent rodent sightings (OR 2·3). Both S. Typhimurium and monophasic S. Typhimurium were more common in duck farms. Isolates had a high prevalence of resistance (77·6%) against tetracycline, moderate resistance (20-30%) against chloramphenicol, sulfamethoxazole-trimethoprim, ampicillin and nalidixic acid, and low resistance (<5%) against ciprofloxacin and third-generation cephalosporins. Multidrug resistance (resistance against ⩾3 classes of antimicrobial) was independently associated with monophasic S. Typhimurium and other group B isolates (excluding S. Typhimurium) and pig farms. The unusually high prevalence of NTS on Mekong Delta farms poses formidable challenges for control

A Mutation in the Transcription Factor Foxp3 Drives T Helper 2 Effector Function in Regulatory T Cells.

Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cell function and homeostasis. We identified an IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome patient with a FOXP3 mutation in the domain swap interface of the protein. Recapitulation of this Foxp3 variant in mice led to the development of an autoimmune syndrome consistent with an unrestrained T helper type 2 (Th2) immune response. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27ac-HiChIP revealed a specific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells. Th2-like Treg cells showed increased intra-chromosomal interactions in the Th2 locus, leading to type 2 cytokine production. These findings identify a direct role for Foxp3 in suppressing Th2-like Treg cells and implicate additional pathways that could be targeted to restrain Th2 trans-differentiated Treg cells