RESUMEN
Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders.
Asunto(s)
Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Discapacidad Intelectual/genética , Empalme Alternativo/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo C/genética , Haploinsuficiencia/genética , Trastornos del Neurodesarrollo/genética , Ribonucleoproteínas Nucleares Heterogéneas/genéticaRESUMEN
We describe clinical details, including novel findings, of two further children with the newly defined TLK2-related disorder. One patient was recruited to the Deciphering Developmental Delay (DDD) Study to identify underlying etiology of global developmental delay. The other was detected on whole-exome sequencing as part of second line investigations following normal microarray. Both patients were found to have de novo heterozygous pathogenic TLK2 variants. A novel c.6del p.(Glu3Lysfs*) loss-of-function frameshift variant was found in Patient 1. A c.1121+1G>A splice-donor variant was detected in Patient 2. TLK2-related neurodevelopmental disorder is a specific syndrome that has been recently described. Global developmental delay, behavioral problems, gastrointestinal disorders, and typical facial dysmorphism are common features. Neuropsychiatric disorders, ophthalmic, musculoskeletal and cranial abnormalities, as well as short stature, have also all been described. The novel findings we describe include sleep disturbance, nondifferentiation of lateral semi-circular canals (where asymmetric semi-circular canals were a feature in the previous cohort), vesico-ureteric reflux, and bilateral periauricular skin tags. Here, we report a novel TLK2 variant and previously undescribed features of TLK2-related disorder, to expand the clinical phenotype and provide further genotype-phenotype correlation.
Asunto(s)
Discapacidad Intelectual , Trastornos del Neurodesarrollo , Niño , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Estudios de Asociación Genética , Heterocigoto , Humanos , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Fenotipo , Secuenciación del ExomaRESUMEN
TAB2 is a gene located on chromosome 6q25.1 and plays a key role in development of the heart. Existing literature describes congenital heart disease as a common recognized phenotype of TAB2 gene variants, with evidence of a distinct syndromic phenotype also existing beyond this. Here we describe 14 newly identified individuals with nine novel, pathogenic TAB2 variants. The majority of individuals were identified through the Deciphering Developmental Disorders study through trio whole exome sequencing. Eight individuals had de novo variants, the other six individuals were found to have maternally inherited, or likely maternally inherited, variants. Five individuals from the same family were identified following cardiac disease gene panel in the proband and subsequent targeted familial gene sequencing. The clinical features of this cohort were compared to the existing literature. Common clinical features include distinctive facial features, growth abnormalities, joint hypermobility, hypotonia, and developmental delay. Newly identified features included feeding difficulties, sleep problems, visual problems, genitourinary abnormality, and other anatomical variations. Here we report 14 new individuals, including novel TAB2 variants, in order to expand the emerging syndromic clinical phenotype and provide further genotype-phenotype correlation.
Asunto(s)
Cardiopatías Congénitas , Discapacidad Intelectual , Proteínas Adaptadoras Transductoras de Señales/genética , Niño , Discapacidades del Desarrollo/genética , Estudios de Asociación Genética , Cardiopatías Congénitas/genética , Humanos , Discapacidad Intelectual/genética , Fenotipo , Secuenciación del ExomaRESUMEN
Pathogenic variants in heterogeneous nuclear ribonucleoprotein U (HNRNPU) results in a novel neurodevelopmental disorder recently delineated. Here, we report on 17 previously unpublished patients carrying HNRNPU pathogenic variants. All patients were found to harbor de novo loss-of-function variants except for one individual where the inheritance could not be determined, as a parent was unavailable for testing. All patients had seizures which started in early childhood, global developmental delay, intellectual disability, and dysmorphic features. In addition, hypotonia, behavioral abnormalities (such as autistic features, aggression, anxiety, and obsessive-compulsive behaviors), and cardiac (septal defects) and/or brain abnormalities (ventriculomegaly and corpus callosum thinning/agenesis) were frequently observed. We have noted four recurrent variants in the literature (c.1089G>A p.(Trp363*), c.706_707del p.(Glu236Thrfs*6), c.847_857del p.(Phe283Serfs*5), and c.1681dels p.(Gln561Serfs*45)).
Asunto(s)
Discapacidad Intelectual , Trastornos del Neurodesarrollo , Agenesia del Cuerpo Calloso/genética , Niño , Preescolar , Discapacidades del Desarrollo/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo U/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Fenotipo , Convulsiones/genéticaRESUMEN
BACKGROUND: Intrapartum antibiotic prophylaxis (IAP) reduces a newborn's risk of group B streptococcal infection (GBS) but may lead to an increased childhood body mass index (BMI). METHODS: This was a retrospective cohort study of infants (nâ =â 223 431) born 2007-2015 in an integrated healthcare system. For vaginal delivery, we compared children exposed to GBS-IAP and to any other type or duration of intrapartum antibiotics to no antibiotic exposure. For cesarean delivery, we compared children exposed to GBS-IAP to those exposed to all other intrapartum antibiotics, including surgical prophylaxis. BMI over 5 years was compared using nonlinear multivariate models with B-spline functions, stratified by delivery mode and adjusted for demographics, maternal factors, breastfeeding, and childhood antibiotic exposure. RESULTS: In vaginal deliveries, GBS-IAP was associated with higher BMI from 0.5 to 5.0 years of age compared to no antibiotics (Pâ <â .0001 for all time points, ΔBMI at age 5 years 0.12 kg/m2, 95% confidence interval [CI]: .07-.16 kg/m2). Other antibiotics were associated with higher BMI from 0.3 to 5.0 years of age. In cesarean deliveries, GBS-IAP was associated with increased BMI from 0.7 years to 5.0 years of age (Pâ <â .05 for 0.7-0.8 years, Pâ <â .0001 for all other time points) compared to other antibiotics (ΔBMI at age 5 years 0.24 kg/m2, 95% CI: .14-.34 kg/m2). Breastfeeding did not modify these associations. CONCLUSIONS: GBS-IAP was associated with a small but sustained increase in BMI starting at very early age. This association highlights the need to better understand the effects of perinatal antibiotic exposure on childhood health.
Asunto(s)
Complicaciones Infecciosas del Embarazo , Infecciones Estreptocócicas , Antibacterianos/efectos adversos , Profilaxis Antibiótica , Índice de Masa Corporal , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Estudios Retrospectivos , Infecciones Estreptocócicas/tratamiento farmacológico , Streptococcus agalactiaeRESUMEN
BACKGROUND: Reported outbreaks of invasive group A Streptococcus (iGAS) infections among people who inject drugs (PWID) and people experiencing homelessness (PEH) have increased, concurrent with rising US iGAS rates. We describe epidemiology among iGAS patients with these risk factors. METHODS: We analyzed iGAS infections from population-based Active Bacterial Core surveillance (ABCs) at 10 US sites from 2010 to 2017. Cases were defined as GAS isolated from a normally sterile site or from a wound in patients with necrotizing fasciitis or streptococcal toxic shock syndrome. GAS isolates were emm typed. We categorized iGAS patients into four categories: injection drug use (IDU) only, homelessness only, both, and neither. We calculated annual change in prevalence of these risk factors using log binomial regression models. We estimated national iGAS infection rates among PWID and PEH. RESULTS: We identified 12â 386 iGAS cases; IDU, homelessness, or both were documented in ~13%. Skin infections and acute skin breakdown were common among iGAS patients with documented IDU or homelessness. Endocarditis was 10-fold more frequent among iGAS patients with documented IDU only versus those with neither risk factor. Average percentage yearly increase in prevalence of IDU and homelessness among iGAS patients was 17.5% and 20.0%, respectively. iGAS infection rates among people with documented IDU or homelessness were ~14-fold and 17- to 80-fold higher, respectively, than among people without those risks. CONCLUSIONS: IDU and homelessness likely contribute to increases in US incidence of iGAS infections. Improving management of skin breakdown and early recognition of skin infection could prevent iGAS infections in these patients.
Asunto(s)
Consumidores de Drogas , Fascitis Necrotizante , Personas con Mala Vivienda , Infecciones Estreptocócicas , Fascitis Necrotizante/epidemiología , Humanos , Infecciones Estreptocócicas/epidemiología , Infecciones Estreptocócicas/microbiología , Streptococcus pyogenes , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Senegal introduced a 13-valent pneumococcal conjugate vaccine (PCV13) in October 2013, given at 6, 10, and 14 weeks of age. We document trends of meningitis and pneumonia after the PCV13 introduction. METHODS: From October 2010-October 2016, hospitalization data for clinical meningitis and pneumonia in children aged <5 years were collected from logbooks at a large, tertiary, pediatric hospital in Dakar. We used a set of predetermined keywords to define hospitalizations for extraction from hospital registers. We conducted a time-series analysis and compared hospitalizations before and after the PCV13 introduction, accounting for seasonality. The initial PCV13 uptake period (October 2013-September 2014) was considered to be transitional and was excluded. RESULTS: Over the 7-year period, 1836 and 889 hospitalizations with a discharge diagnosis of pneumonia and meningitis, respectively, occurred in children aged <5 years. In children aged <12 months, a small, significant reduction in pneumonia was observed post-PCV13 (-3.8%, 95% confidence interval [CI] -1.5 to -5.9%). No decline was observed among children aged 12-59 months (-0.7%, 95% CI -0.8 to 2.2%). Meningitis hospitalizations remained stable for children aged <12 months (1.8%, 95% CI -0.9 to 4.4%) and 12-59 months (-0.5%, 95% CI -3.6 to 2.6%). CONCLUSIONS: We used data from 1 hospital to detect a small, significant reduction in all-cause pneumonia hospitalizations 2 years post-PCV13 introduction in infants; the same trend was not measurable in children aged 12-59 months or in meningitis cases. There is a need for continued surveillance to assess the long-term impact of sustained PCV13 use and to monitor how pneumococcus is causing disease in the meningitis belt.
Asunto(s)
Hospitalización/estadística & datos numéricos , Meningitis Bacterianas/epidemiología , Vacunas Neumococicas/administración & dosificación , Neumonía Neumocócica/epidemiología , Sistema de Registros , Preescolar , Hospitales Pediátricos/estadística & datos numéricos , Humanos , Lactante , Meningitis Bacterianas/prevención & control , Neumonía Neumocócica/prevención & control , Senegal/epidemiología , Vacunas Conjugadas/administración & dosificaciónRESUMEN
BACKGROUND: In January 2015, a total of 11 new diagnoses of human immunodeficiency virus (HIV) infection were reported in a small community in Indiana. We investigated the extent and cause of the outbreak and implemented control measures. METHODS: We identified an outbreak-related case as laboratory-confirmed HIV infection newly diagnosed after October 1, 2014, in a person who either resided in Scott County, Indiana, or was named by another case patient as a syringe-sharing or sexual partner. HIV polymerase (pol) sequences from case patients were phylogenetically analyzed, and potential risk factors associated with HIV infection were ascertained. RESULTS: From November 18, 2014, to November 1, 2015, HIV infection was diagnosed in 181 case patients. Most of these patients (87.8%) reported having injected the extended-release formulation of the prescription opioid oxymorphone, and 92.3% were coinfected with hepatitis C virus. Among 159 case patients who had an HIV type 1 pol gene sequence, 157 (98.7%) had sequences that were highly related, as determined by phylogenetic analyses. Contact tracing investigations led to the identification of 536 persons who were named as contacts of case patients; 468 of these contacts (87.3%) were located, assessed for risk, tested for HIV, and, if infected, linked to care. The number of times a contact was named as a syringe-sharing partner by a case patient was significantly associated with the risk of HIV infection (adjusted risk ratio for each time named, 1.9; P<0.001). In response to this outbreak, a public health emergency was declared on March 26, 2015, and a syringe-service program in Indiana was established for the first time. CONCLUSIONS: Injection-drug use of extended-release oxymorphone within a network of persons who inject drugs in Indiana led to the introduction and rapid transmission of HIV. (Funded by the state government of Indiana and others.).
Asunto(s)
Brotes de Enfermedades , Infecciones por VIH/epidemiología , VIH-1/genética , Oximorfona/administración & dosificación , Abuso de Sustancias por Vía Intravenosa/complicaciones , Adolescente , Adulto , Coinfección , Trazado de Contacto , Infecciones por VIH/transmisión , Hepatitis C/epidemiología , Humanos , Indiana/epidemiología , Masculino , Persona de Mediana Edad , Compartición de Agujas/efectos adversos , Filogenia , Apoyo Social , Adulto JovenRESUMEN
In the United States, 9% of human immunodeficiency virus (HIV) infections diagnosed in 2015 were attributed to injection drug use (1). In 2015, 79% of diagnoses of HIV infection among persons who inject drugs occurred in urban areas (2). To monitor the prevalence of HIV infection and associated behaviors among persons who inject drugs, CDC's National HIV Behavioral Surveillance (NHBS) conducts interviews and HIV testing in selected metropolitan statistical areas (MSAs) (3). The prevalence of HIV infection among persons who inject drugs in 20 MSAs in 2015 was 7%. In a behavioral analysis of HIV-negative persons who inject drugs, an estimated 27% receptively shared syringes and 67% had condomless vaginal sex in the previous 12 months. During the same period, 58% had tested for HIV infection and 52% received syringes from a syringe services program. Given the increased number of persons newly injecting drugs who are at risk for HIV infection because of the recent opioid epidemic (2,4), these findings underscore the importance of continuing and expanding health services, HIV prevention programs, and community-based strategies, such as those provided by syringe services programs, for this population.
Asunto(s)
Ciudades , Infecciones por VIH/epidemiología , Asunción de Riesgos , Abuso de Sustancias por Vía Intravenosa/epidemiología , Adolescente , Adulto , Negro o Afroamericano/psicología , Negro o Afroamericano/estadística & datos numéricos , Sistema de Vigilancia de Factor de Riesgo Conductual , Femenino , Infecciones por VIH/etnología , Hispánicos o Latinos/psicología , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores Socioeconómicos , Abuso de Sustancias por Vía Intravenosa/etnología , Estados Unidos/epidemiología , Población Blanca/psicología , Población Blanca/estadística & datos numéricos , Adulto JovenRESUMEN
In January 2015, an outbreak of undiagnosed human immunodeficiency virus (HIV) infections among persons who inject drugs (PWID) was recognized in rural Indiana. By September 2016, 205 persons in this community of approximately 4400 had received a diagnosis of HIV infection. We report results of new approaches to analyzing epidemiologic and laboratory data to understand transmission during this outbreak. HIV genetic distances were calculated using the polymerase region. Networks were generated using data about reported high-risk contacts, viral genetic similarity, and their most parsimonious combinations. Sample collection dates and recency assay results were used to infer dates of infection. Epidemiologic and laboratory data each generated large and dense networks. Integration of these data revealed subgroups with epidemiologic and genetic commonalities, one of which appeared to contain the earliest infections. Predicted infection dates suggest that transmission began in 2011, underwent explosive growth in mid-2014, and slowed after the declaration of a public health emergency. Results from this phylodynamic analysis suggest that the majority of infections had likely already occurred when the investigation began and that early transmission may have been associated with sexual activity and injection drug use. Early and sustained efforts are needed to detect infections and prevent or interrupt rapid transmission within networks of uninfected PWID.
Asunto(s)
Brotes de Enfermedades , Infecciones por VIH/genética , Infecciones por VIH/transmisión , VIH-1/genética , Alcaloides Opiáceos/efectos adversos , Abuso de Sustancias por Vía Intravenosa/complicaciones , Adulto , Trazado de Contacto , Femenino , Infecciones por VIH/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Conducta Sexual , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Annual human immunodeficiency virus (HIV) testing is considered a key strategy for HIV prevention for men who have sex with men (MSM). In Puerto Rico, HIV research has primarily focused on injection drug use, yet male-to-male sexual transmission has been increasing in recent years. METHODS: Cross-sectional data from the National HIV Behavioral Surveillance system collected in 2011 in San Juan, Puerto Rico, were analyzed to identify factors associated with HIV testing in the past 12 months (recent testing). RESULTS: Overall, 50% of participants were tested recently. In the multivariate analysis, testing recently was associated with having multiple partners in the past 12 months (adjusted prevalence ratio [aPR] [≥4 vs 1 partner] = 1.5; 95% confidence interval [95% CI], 1.2-2.0), visiting a health care provider in the past 12 months (aPR, 1.4; 95% CI, 1.04-1.8), and disclosing male-male attraction/sex to a health care provider (aPR< 1.4; 95% CI, 1.1-1.7). CONCLUSIONS: Human immunodeficiency virus testing was suboptimal among MSM in San Juan. Strategies to increase HIV testing among MSM may include promoting HIV testing for all sexually active MSM including those with fewer partners, increasing utilization of the healthcare system, and improving patient-provider communication.
Asunto(s)
Infecciones por VIH/diagnóstico , Minorías Sexuales y de Género , Abuso de Sustancias por Vía Intravenosa , Adolescente , Adulto , Estudios Transversales , Monitoreo Epidemiológico , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Homosexualidad Masculina , Humanos , Masculino , Tamizaje Masivo , Prevalencia , Puerto Rico , Conducta Sexual , Parejas Sexuales , Adulto JovenRESUMEN
In the United States, an estimated 7% of new diagnoses of human immunodeficiency virus (HIV) infection in 2012 were attributed to injection drug use, and an additional 3% to male-to-male sexual contact and injection drug use. To monitor HIV prevalence and behaviors associated with HIV risk and prevention among persons who inject drugs (PWID), CDC's National HIV Behavioral Surveillance (NHBS) system conducts interviews and HIV testing in selected cities. This report summarizes HIV prevalence and behaviors among PWID interviewed and tested in 20 cities in 2012. Of the 10,002 PWID tested, 11% had a positive HIV test result. Among 9,425 PWID included in the behavioral analysis, 30% receptively shared syringes, 70% had vaginal sex without a condom, 25% had heterosexual anal sex without a condom, and 5% of males had male-to-male sexual contact without a condom in the previous 12 months. Fifty-one percent of PWID included in the behavioral analysis had been tested for HIV, 25% participated in an HIV behavioral intervention, and 39% participated in substance abuse treatment in the previous 12 months. Additional efforts are needed to reduce risk behaviors and increase access to HIV testing, drug treatment, and other HIV prevention programs to further reduce HIV infections among PWID.
Asunto(s)
Ciudades , Infecciones por VIH/epidemiología , Asunción de Riesgos , Abuso de Sustancias por Vía Intravenosa/epidemiología , Adolescente , Adulto , Negro o Afroamericano/psicología , Negro o Afroamericano/estadística & datos numéricos , Sistema de Vigilancia de Factor de Riesgo Conductual , Femenino , Infecciones por VIH/etnología , Hispánicos o Latinos/psicología , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores Socioeconómicos , Abuso de Sustancias por Vía Intravenosa/etnología , Estados Unidos/epidemiología , Población Blanca/psicología , Población Blanca/estadística & datos numéricos , Adulto JovenRESUMEN
Erv1 (essential for respiration and viability 1) is an FAD-dependent thiol oxidase of the Erv/ALR (augmenter of liver regeneration) sub-family. It is an essential component of the mitochondrial import and assembly (MIA) pathway, playing an important role in the oxidative folding of the mitochondrial intermembrane space (IMS) proteins and linking the MIA pathway to the mitochondrial respiratory chain via cytochrome c (cyt c). The importance of the Erv/ALR enzymes was also demonstrated in a recent study where a single mutation in the human ALR (R194H) leads to autosomal recessive myopathy [Di Fonzo, Ronchi, Lodi, Fassone, Tigano, Lamperti, Corti, Bordoni, Fortunato, Nizzardo et al. (2009) Am. J. Hum. Genet. 84, 594-604]. However, the molecular mechanism of the disease is still unclear. In the present study, we use yeast Erv1 as a model to provide clear evidence for a progressive functional defect in the catalytic activity of the corresponding Erv1 R182H mutant. We show that the FAD cofactor was released from Erv1 R182H during its catalytic cycle, which led to the inactivation of the enzyme. We also characterized the effects of the mutation on the folding and stability of Erv1 and tested our in vitro findings in vivo using a yeast genetic approach. The results of the present study allow us to provide a model for the functional defect in Erv1 R182H, which could potentially be extended to human ALR R194H and provides insights into the molecular basis of autosomal recessive myopathy.
Asunto(s)
Reductasas del Citocromo/genética , Reductasas del Citocromo/metabolismo , Enfermedades Musculares/genética , Mutación Missense , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Catálisis , Dominio Catalítico/genética , Coenzimas/metabolismo , Reductasas del Citocromo/química , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Unión Proteica , Estructura Terciaria de Proteína/genética , Homología de Secuencia de AminoácidoRESUMEN
This study compared HIV sero-prevalence and risk behaviors between younger and older injecting drug users (IDUs). IDUs aged ≥18 years were interviewed for the 2009 National HIV Behavioral Surveillance System. Using GEE regression, we assessed characteristics of younger (18-29 years) and older (≥30 years) IDUs, and factors associated with past 12-month receptive syringe sharing and unprotected sex (vaginal/anal). Of 10,090 participants, 10 % were younger. HIV sero-prevalence was lower among younger than older IDUs (4 vs. 10 %, p = 0.001). Younger IDUs were more likely (p ≤ 0.002) to be non-black race/ethnicity, report higher household income, homelessness, being arrested and to engage in receptive syringe sharing and unprotected sex. In multivariable models, age remained associated (p < 0.001) with receptive syringe sharing (aPR = 1.14, 95 % CI1.07-1.22) and unprotected sex (aPR = 1.10, 95 % CI1.06-1.14). Although younger IDUs had lower HIV prevalence, their behaviors place them at increased risk of HIV infection and could lead to a rapid spread in this susceptible population.
Asunto(s)
Consumidores de Drogas/estadística & datos numéricos , Infecciones por VIH/epidemiología , Asunción de Riesgos , Abuso de Sustancias por Vía Intravenosa/epidemiología , Sexo Inseguro , Adulto , Distribución por Edad , Factores de Edad , Sistema de Vigilancia de Factor de Riesgo Conductual , Estudios Transversales , Consumidores de Drogas/psicología , Femenino , Humanos , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Análisis Multivariante , Compartición de Agujas , Estudios Seroepidemiológicos , Factores Socioeconómicos , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Mia40 is a highly conserved mitochondrial protein that plays an essential role in the import and oxidative folding of many proteins of the mitochondrial intermembrane space. Mia40 uses its redox active CPC motif to shuttle disulfides between its client proteins (newly imported proteins) and the thiol oxidase Erv1. As a thiol oxidoreductase, no cofactor was found in Mia40, nor is a cofactor required for this function. In the present study we, for the first time based on both in vitro and in vivo studies, show that yeast Mia40 can exist as an Fe-S (iron-sulfur) protein as well. We show that Mia40 binds a [2Fe-2S] cluster in a dimer form with the cluster co-ordinated by the cysteine residues of the CPC motifs. The biological relevance of the cofactor binding was confirmed in vivo by cysteine redox state and iron uptake analyses, which showed that a significant amount of cellular Mia40 binds iron in vivo. Furthermore, our oxygen consumption results suggested that the Fe-S-containing Mia40 is not an electron donor for Erv1. Thus we conclude that Mia40 is a novel Fe-S protein with a new cluster-binding motif (CPC), and apart from the thiol oxidoreductase activity, Mia40 may have another important, as yet undefined, function in cells.
Asunto(s)
Proteínas Hierro-Azufre/química , Hierro/química , Mitocondrias/química , Proteínas de Transporte de Membrana Mitocondrial/química , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/química , Sitios de Unión , Escherichia coli/genética , Escherichia coli/metabolismo , Hierro/metabolismo , Proteínas Hierro-Azufre/genética , Proteínas Hierro-Azufre/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Oxidación-Reducción , Unión Proteica , Multimerización de Proteína , Estabilidad Proteica , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMEN
Correct and timely folding is critical to the function of all proteins. The importance of this is illustrated in the biogenesis of the mitochondrial intermembrane space (IMS) "small Tim" proteins. Biogenesis of the small Tim proteins is regulated by dedicated systems or pathways, beginning with synthesis in the cytosol and ending with assembly of individually folded proteins into functional complexes in the mitochondrial IMS. The process is mostly centered on regulating the redox states of the conserved cysteine residues: oxidative folding is crucial for protein function in the IMS, but oxidized (disulfide bonded) proteins cannot be imported into mitochondria. How the redox-sensitive small Tim precursor proteins are maintained in a reduced, import-competent form in the cytosol is not well understood. Recent studies suggest that zinc and the cytosolic thioredoxin system play a role in the biogenesis of these proteins. In the IMS, the mitochondrial import and assembly (MIA) pathway catalyzes both import into the IMS and oxidative folding of the small Tim proteins. Finally, assembly of the small Tim complexes is a multistep process driven by electrostatic and hydrophobic interactions; however, the chaperone function of the complex might require destabilization of these interactions to accommodate the substrate. Here, we review how folding of the small Tim proteins is regulated during their biogenesis, from maintenance of the unfolded precursors in the cytosol, to their import, oxidative folding, complex assembly and function in the IMS.
Asunto(s)
Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Pliegue de Proteína , Proteínas de Saccharomyces cerevisiae/metabolismo , Secuencia de Aminoácidos , Interacciones Hidrofóbicas e Hidrofílicas , Proteínas de la Membrana/biosíntesis , Proteínas de Transporte de Membrana Mitocondrial/biosíntesis , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Datos de Secuencia Molecular , Oxidación-Reducción , Oxidorreductasas/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/biosíntesis , Electricidad EstáticaRESUMEN
Individuals with biallelic TBCK pathogenic variants present in infancy with distinctive facial features, profound hypotonia, severe intellectual impairment and epilepsy. Although rare, it may mimic other neurogenetic disorders leading to extensive investigations. Improved understanding of the clinical phenotype can support early monitoring of complications due to respiratory insufficiency. We present six individuals who were found to have pathogenic biallelic TBCK variants. The clinico-radiological and diagnostic records were reviewed. Five individuals were diagnosed with hypoventilation, requiring respiratory support, highlighting the need for early respiratory surveillance. Characteristic brain imaging in our cohort included periventricular leukomalacia-like changes. We recommend screening for TBCK in hypotonic children with periventricular leukomalacia-like changes, particularly in the absence of prematurity.
Asunto(s)
Leucomalacia Periventricular , Proteínas Serina-Treonina Quinasas , Humanos , Encéfalo , Hipoventilación/diagnóstico , Hipoventilación/genética , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , NiñoRESUMEN
Importance: The association of 13-valent pneumococcal conjugate vaccine (PCV13) use with pneumonia hospitalization in older adults, especially those with underlying medical conditions, is not well described. Objective: To evaluate the association of PCV13 use with pneumonia, non-health care-associated (non-HA) pneumonia, and lobar pneumonia (LP) hospitalization among US Medicare beneficiaries 65 years or older. Design, Setting, and Participants: This cohort study with time-varying exposure assignment analyzed claims data from US Medicare beneficiaries 65 years or older enrolled in Parts A/B with a residence in the 50 US states or the District of Columbia by September 1, 2014. New Medicare Parts A/B beneficiaries within 6 months after their 65th birthday were continuously included in the cohort after September 1, 2014, and followed through December 31, 2017. Participants were censored if they died, changed enrollment status, or developed a study outcome. Most of the analyses were conducted from 2018 to 2019, and additional analyses were performed from 2021 to 2022. Exposures: Use of PCV13 vaccination 14 days or more before pneumonia hospitalization. Main Outcomes and Measures: Discrete-time survival models were used to estimate the incidence rate ratio (IRR) and number of pneumonia hospitalizations averted through PCV13 use. The adjusted IRR for the association of PCV13 vaccination with pneumonia hospitalization was used to estimate vaccine effectiveness (VE). Results: At the end of follow-up (December 2017), 24â¯121â¯625 beneficiaries (13â¯593â¯975 women [56.4%]; 418â¯005 [1.7%] Asian, 1â¯750â¯807 [4.8%] Black, 338â¯044 [1.4%] Hispanic, 111â¯508 [0.5%] Native American, and 20â¯700â¯948 [85.8%] White individuals) were in the cohort; 4â¯936â¯185 (20.5%) had received PCV13 only, and 10â¯646â¯220 (79.5%) had not received any pneumococcal vaccines. More than half of the beneficiaries in the cohort were younger than 75 years, White, and had either immunocompromising or chronic medical conditions. Coverage with PCV13 increased from 0.8% (September 2014) to 41.5% (December 2017). The VE for PCV13 was estimated at 6.7% (95% CI, 5.9%-7.5%) for pneumonia, 4.7% (95% CI, 3.9%-5.6%) for non-HA pneumonia, and 5.8% (95% CI, 2.6%-8.9%) for LP. From September 2014 through December 2017, an estimated 35â¯127 pneumonia (95% CI, 33â¯011-37â¯270), 24â¯643 non-HA pneumonia (95% CI, 22â¯761-26â¯552), and 1294 LP (95% CI, 797-1819) hospitalizations were averted through PCV13 use. Conclusions and Relevance: The study results suggest that PCV13 use was associated with reduced pneumonia hospitalization among Medicare beneficiaries 65 years or older, many of whom had underlying medical conditions. Increased PCV13 coverage and use of recently approved higher-valent pneumococcal conjugate vaccines may avert additional pneumonia hospitalizations in adults.
Asunto(s)
Neumonía Neumocócica , Streptococcus pneumoniae , Anciano , Humanos , Femenino , Estados Unidos/epidemiología , Streptococcus pneumoniae/inmunología , Vacunas Conjugadas/uso terapéutico , Vacunas Conjugadas/inmunología , Estudios de Cohortes , Eficacia de las Vacunas , Medicare , Neumonía Neumocócica/epidemiología , Neumonía Neumocócica/prevención & control , Neumonía Neumocócica/inmunología , Vacunación/métodos , Vacunas NeumococicasRESUMEN
Protein translocation across the endoplasmic reticulum membrane occurs via a "translocon" channel formed by the Sec61p complex. In yeast, two channels exist: the canonical Sec61p channel and a homolog called Ssh1p. Here, we used trapped translocation intermediates to demonstrate that a specific signal recognition particle-dependent substrate, Sec71p, is targeted exclusively to Ssh1p. Strikingly, we found that, in the absence of Ssh1p, precursor could be successfully redirected to canonical Sec61p, demonstrating that the normal targeting reaction must involve preferential sorting to Ssh1p. Our data therefore demonstrate that Ssh1p is the primary translocon for Sec71p and reveal a novel sorting mechanism at the level of the endoplasmic reticulum membrane enabling precursors to be directed to distinct translocons. Interestingly, the Ssh1p-dependent translocation of Sec71p was found to be dependent upon Sec63p, demonstrating a previously unappreciated functional interaction between Sec63p and the Ssh1p translocon.
Asunto(s)
Proteínas de la Membrana/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Partícula de Reconocimiento de Señal/metabolismo , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Proteínas de la Membrana/química , Estructura Terciaria de Proteína , Transporte de Proteínas , Proteínas de Saccharomyces cerevisiae/química , Especificidad por SustratoRESUMEN
Diaphonospondylodysotosis (DSD) and ischiospinal dysostosis (ISD) are rare skeletal dysplasias with variants in the bone morphogenetic protein-binding endothelial regulator (BMPER). There is a continuum of clinical presentation, with DSD at the severe end of the spectrum whilst ISD is towards the milder end. Both are caused due to pathogenic variants in BMPER. Previous studies have reported 20 patients from 13 families. Common features in the cohort reported so far are spinal and rib anomalies but other findings illustrate phenotypic variation. Survival ranges from death within the neonatal period to alive and well at 19 years. We present three siblings with variable phenotype, adding to the evidence for a single definition of BMPER-related skeletal dysplasia. We highlight the need for ongoing care planning and guarded prognostication, with regular review by clinical teams.