Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease.

IntroductionMedia interventions can potentially play a major role in influencing health policies. This integrative systematic review aimed to assess the effects of planned media interventions—including social media—on the health policy-making process.MethodsEligible study designs included randomized and non-randomized designs, economic studies, process evaluation studies, stakeholder analyses, qualitative methods, and case studies. We electronically searched Medline, EMBASE, Communication and Mass Media Complete, Cochrane Central Register of Controlled Trials, and the WHO Global Health Library. We followed standard systematic review methodology for study selection, data abstraction, and risk of bias assessment.ResultsTwenty-one studies met our eligibility criteria: 10 evaluation studies using either quantitative (n = 7) or qualitative (n = 3) designs and 11 case studies. None of the evaluation studies were on social media. The findings of the evaluation studies suggest that media interventions may have a positive impact when used as accountability tools leading to prioritizing and initiating policy discussions, as tools to increase policymakers’ awareness, as tools to influence policy formulation, as awareness tools leading to policy adoption, and as awareness tools to improve compliance with laws and regulations. In one study, media-generated attention had a negative effect on policy advocacy as it mobilized opponents who defeated the passage of the bills that the media intervention advocated for. We judged the confidence in the available evidence as limited due to the risk of bias in the included studies and the indirectness of the evidence.ConclusionThere is currently a lack of reliable evidence to guide decisions on the use of media interventions to influence health policy-making. Additional and better-designed, conducted, and reported primary research is needed to better understand the effects of media interventions, particularly social media, on health policy-making processes, and the circumstances under which media interventions are successful.Trial registrationPROSPERO 2015:CRD42015020243 Electronic supplementary materialThe online version of this article (doi:10.1186/s13012-017-0581-0) contains supplementary material, which is available to authorized users.

We describe a novel autosomal recessive form of mitochondrial disease in a child with short stature, poor weight gain, and mild dysmorphic features with highly suspected Fanconi anemia due to a mutation in COX4I1 gene. Whole Exome Sequencing was performed then followed by Sanger confirmation, identified a K101N mutation in COX4I1, segregating with the disease. This nuclear gene encodes the common isoform of cytochrome c oxidase (COX) subunit 4 (COX 4-1), an integral regulatory part of COX (respiratory chain complex IV) the terminal electron acceptor of the mitochondrial respiratory chain. The patient's fibroblasts disclosed decreased COX activity, impaired ATP production, elevated ROS production, decreased expression of COX4I1 mRNA and undetectable (COX4) protein. COX activity and ATP production were restored by lentiviral transfection with the wild-type gene. Our results demonstrate the first human mutation in the COX4I1 gene linked to diseases and confirm its role in the pathogenesis. Thus COX4I1 mutations should be considered in any patient with features suggestive of this diagnosis.

Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, Gly372Ser, in the TIMM50 gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3-methylglutaconic aciduria. We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3-methylglutaconic aciduria and variable deficiency of mitochondrial complex V. Using exome analysis we identified two homozygous missense mutations, Arg217Trp and Thr252Met, in the TIMM50 gene. The TIMM50 protein is a subunit of TIM23 complex, the mitochondrial import machinery. It serves as the major receptor in the intermembrane space, binding to proteins which cross the mitochondrial inner membrane on their way to the matrix. The mutations, which affected evolutionary conserved residues and segregated with the disease in the families, were neither present in large cohorts of control exome analyses nor in our ethnic specific exome cohort. Given the phenotypic similarity, we conclude that missense mutations in TIMM50 are likely manifesting by severe intellectual disability and epilepsy accompanied by 3-methylglutaconic aciduria and variable mitochondrial complex V deficiency. 3-methylglutaconic aciduria is emerging as an important biomarker for mitochondrial dysfunction, in particular for mitochondrial membrane defects.