Island hitchhikers: pathogen agents of Madeira and Azores ticks.

Ticks are blood-sucking arthropods that can transmit pathogens to their host. As insular ecosystems can enhance tick-host interactions, this study aimed to understand tick diversity, pathogen presence, and their respective associations in the Azores and Madeira archipelagos. Unfed or partially engorged ticks (n = 120) were collected from 58 cats and dogs in the Azores (n = 41 specimens) and Madeira (n = 79 specimens) from November 2018 to March 2019. Vector identification was based on morphology and molecular criteria. For pathogen sequencing, 18S gene fragment for Babesia/Hepatozoon and gltA for Rickettsia were performed. Sequence data was explored using BLAST and BLAST and phylogenetic inference tools. In the Azores, Ixodes hexagonus, I. ventalloi, and Rhipicephalus sanguineus (n = 6; 14.6%, n = 6; 14.6%, and n = 29; 70.7% respectively) were found and in Madeira I. ricinus and R. sanguineus (n = 78, 98.7%; and n = 1, 1.3%; respectively) were identified. Tick COI markers confirmed species highlighting confirmation of R. sanguineus s.s. and genotype A of I. ventalloi. In the Azores Islands, the detected Rickettsia massiliae was linked to R. sanguineus (dogs and cats) and I. hexagonus (dogs), and in Madeira Island, R. monacensis (dogs) and Hepatozoon silvestris (cats) were found associated with I. ricinus. Further, I. ventalloi presence in the Azores expands west its known range, and Hepatozoon silvestris in Madeira may suggest that I. ricinus could have a role as a potential vector. Finally, as R. massiliae and R. monacensis presence underlines public health risks, surveillance by health authorities is crucial as pathogen-tick interactions may drive disease spread, therefore monitoring remains pivotal for disease prevention.

A functional survey of the regulatory landscape of estrogen-receptor-positive breast cancer evolution.

Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer (HDBC), potentially explaining ~40% of relapses. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CREs) to cancer evolution by focusing on 12 megabases of non-coding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of non-coding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies triggers the emergence of transient features which could ultimately be exploited to hinder the adaptive process.

Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers.

The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP-TEAD protein-protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.

D6PK plasma membrane polarity requires a repeated CXX(X)P motif and PDK1-dependent phosphorylation.

D6 PROTEIN KINASE (D6PK) is a polarly localized plasma-membrane-associated kinase from Arabidopsis thaliana that activates polarly distributed PIN-FORMED auxin transporters. D6PK moves rapidly to and from the plasma membrane, independent of its PIN-FORMED targets. The middle D6PK domain, an insertion between kinase subdomains VII and VIII, is required and sufficient for association and polarity of the D6PK plasma membrane. How D6PK polarity is established and maintained remains to be shown. Here we show that cysteines from repeated middle domain CXX(X)P motifs are S-acylated and required for D6PK membrane association. While D6PK S-acylation is not detectably regulated during intracellular transport, phosphorylation of adjacent serine residues, in part in dependence on the upstream 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE, promotes D6PK transport, controls D6PK residence time at the plasma membrane and prevents its lateral diffusion. We thus identify new mechanisms for the regulation of D6PK plasma membrane interaction and polarity.

Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens.

YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, in Uveal Melanoma (UM), YAP is activated in a Hippo-independent manner. To date, it is unclear if and how the different oncogenic lesions activating YAP impact its oncogenic program, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, despite YAP being essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. Systematic functional interrogation of YAP regulatory elements in both cancer types reveals convergent regulation of broad oncogenic drivers in both MPM and UM, but also strikingly selective programs. Our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types.

The SCL30a SR protein regulates ABA-dependent seed traits and germination under stress.

SR proteins are conserved RNA-binding proteins best known as splicing regulators that have also been implicated in other steps of gene expression. Despite mounting evidence for a role in plant development and stress responses, the molecular pathways underlying SR protein regulation of these processes remain poorly understood. Here we show that the plant-specific SCL30a SR protein negatively regulates ABA signaling to control seed traits and stress responses during germination in Arabidopsis. Transcriptome-wide analyses revealed that loss of SCL30a function barely affects splicing, but largely induces ABA-responsive gene expression and genes repressed during germination. Accordingly, scl30a mutant seeds display delayed germination and hypersensitivity to ABA and high salinity, while transgenic plants overexpressing SCL30a exhibit reduced ABA and salt stress sensitivity. An ABA biosynthesis inhibitor rescues the enhanced mutant seed stress sensitivity, and epistatic analyses confirm that this hypersensitivity requires a functional ABA pathway. Finally, seed ABA levels are unchanged by altered SCL30a expression, indicating that the gene promotes seed germination under stress by reducing sensitivity to the phytohormone. Our results reveal a new player in ABA-mediated control of early development and stress response.

Directed growth and fusion of membrane-wall microdomains requires CASP-mediated inhibition and displacement of secretory foci.

Casparian strips (CS) are aligned bands of lignin-impregnated cell walls, building an extracellular diffusion barrier in roots. Their structure profoundly differs from tight junctions (TJ), analogous structures in animals. Nonetheless, CS membrane domain (CSD) proteins 1-5 (CASP1-5) are homologues of occludins, TJ components. CASP-marked membranes display cell wall (matrix) adhesion and membrane protein exclusion. A full CASP knock-out now reveals CASPs are not needed for localized lignification, since correctly positioned lignin microdomains still form in the mutant. Ultra-structurally, however, these microdomains are disorganized, showing excessive cell wall growth, lack of exclusion zone and matrix adhesion, and impaired exocyst dynamics. Proximity-labelling identifies a Rab-GTPase subfamily, known exocyst activators, as potential CASP-interactors and demonstrate their localization and function at the CSD. We propose that CASP microdomains displace initial secretory foci by excluding vesicle tethering factors, thereby ensuring rapid fusion of microdomains into a membrane-cell wall band that seals the extracellular space.

Nonadherence to systemic immune-modifying therapy in people with psoriasis during the COVID-19 pandemic: findings from a global cross-sectional survey.

BACKGROUND: Nonadherence to immune-modifying therapy is a complex behaviour which, before the COVID-19 pandemic, was shown to be associated with mental health disorders in people with immune-mediated diseases. The COVID-19 pandemic has led to a rise in the global prevalence of anxiety and depression, and limited data exist on the association between mental health and nonadherence to immune-modifying therapy during the pandemic. OBJECTIVES: To assess the extent of and reasons underlying nonadherence to systemic immune-modifying therapy during the COVID-19 pandemic in individuals with psoriasis, and the association between mental health and nonadherence. METHODS: Online self-report surveys (PsoProtectMe), including validated screens for anxiety and depression, were completed globally during the first year of the pandemic. We assessed the association between anxiety or depression and nonadherence to systemic immune-modifying therapy using binomial logistic regression, adjusting for potential cofounders (age, sex, ethnicity, comorbidity) and country of residence. RESULTS: Of 3980 participants from 77 countries, 1611 (40.5%) were prescribed a systemic immune-modifying therapy. Of these, 408 (25.3%) reported nonadherence during the pandemic, most commonly due to concerns about their immunity. In the unadjusted model, a positive anxiety screen was associated with nonadherence to systemic immune-modifying therapy [odds ratio (OR) 1.37, 95% confidence interval (CI) 1.07-1.76]. Specifically, anxiety was associated with nonadherence to targeted therapy (OR 1.41, 95% CI 1.01-1.96) but not standard systemic therapy (OR 1.16, 95% CI 0.81-1.67). In the adjusted model, although the directions of the effects remained, anxiety was not significantly associated with nonadherence to overall systemic (OR 1.20, 95% CI 0.92-1.56) or targeted (OR 1.33, 95% CI 0.94-1.89) immune-modifying therapy. A positive depression screen was not strongly associated with nonadherence to systemic immune-modifying therapy in the unadjusted (OR 1.22, 95% CI 0.94-1.57) or adjusted models (OR 1.14, 95% CI 0.87-1.49). CONCLUSIONS: These data indicate substantial nonadherence to immune-modifying therapy in people with psoriasis during the pandemic, with attenuation of the association with mental health after adjusting for confounders. Future research in larger populations should further explore pandemic-specific drivers of treatment nonadherence. Clear communication of the reassuring findings from population-based research regarding immune-modifying therapy-associated adverse COVID-19 risks to people with psoriasis is essential, to optimize adherence and disease outcomes.

Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove.

Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6-36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.

EVI1 drives leukemogenesis through aberrant ERG activation.

Chromosomal rearrangements involving the MDS1 and EVI1 complex locus (MECOM) on chromosome 3q26 define an aggressive subtype of acute myeloid leukemia (AML) that is associated with chemotherapy resistance and dismal prognosis. Established treatment regimens commonly fail in these patients, therefore, there is an urgent need for new therapeutic concepts that will require a better understanding of the molecular and cellular functions of the ecotropic viral integration site 1 (EVI1) oncogene. To characterize gene regulatory functions of EVI1 and associated dependencies in AML, we developed experimentally tractable human and murine disease models, investigated the transcriptional consequences of EVI1 withdrawal in vitro and in vivo, and performed the first genome-wide CRISPR screens in EVI1-dependent AML. By integrating conserved transcriptional targets with genetic dependency data, we identified and characterized the ETS transcription factor ERG as a direct transcriptional target of EVI1 that is aberrantly expressed and selectively required in both human and murine EVI1-driven AML. EVI1 controls the expression of ERG and occupies a conserved intragenic enhancer region in AML cell lines and samples from patients with primary AML. Suppression of ERG induces terminal differentiation of EVI1-driven AML cells, whereas ectopic expression of ERG abrogates their dependence on EVI1, indicating that the major oncogenic functions of EVI1 are mediated through aberrant transcriptional activation of ERG. Interfering with this regulatory axis may provide entry points for the development of rational targeted therapies.

Seroprevalence and Risk Factors Associated with Leishmania Infection in Dogs from Portugal.

Canine leishmaniosis (CanL) caused by Leishmania infantum is an important zoonosis in southwestern European countries where this disease is endemic, and dogs, as domestic animals in close contact with humans, are the reservoir hosts for the parasite. In Portugal, CanL is of relevant veterinary concern. The previous national study revealed an overall seroprevalence of 6.3%. Since then, new prophylactic measures, such as vaccines, have been introduced in Europe. The aim of this study was to update seroprevalence for Leishmania infection and reassess risk factors in Portugal. A cross-sectional study was conducted from January-March 2021 with 1860 client-owned dogs from continental Portugal. A questionnaire and whole blood samples on filter paper were collected and a direct agglutination test was used to calculate anti-Leishmania antibody titres. True seroprevalence was 12.5% (95% CI 10.3-13.2%). Potential risk factors associated with L. infantum infection in dogs were age ≥ 2 years (aOR = 1.68, 95% CI 1.1-2.6) and residing in the interior regions of the country (aOR = 1.92, 95% CI 1.3-2.9) and non-use of repellents (aOR = 1.75, 95% CI 1.2-2.5). The key to controlling CanL and its impact on Public Health in endemic areas lies in continuous implementation of prophylactic measures, through the correct use of repellents/insecticides and vaccines and early detection and monitoring of infected dogs.

Beyond width and density: stable carbon and oxygen isotopes in cork-rings provide insights of physiological responses to water stress in Quercus suber L.

As climate change increasingly affects forest ecosystems, detailed understanding of major effects is important to anticipate their consequences under future climate scenarios. The Mediterranean region is a prominent climate change hotspot, and evergreen cork oak (Quercus suber L.) woodlands are particularly climatically sensitive due to cork (bark) harvesting. Cork oak's drought avoidance strategy is well-known and includes structural and physiological adaptations that maximise soil water uptake and transport and limit water use, potentially leading to reduced stem and cork growth. Trees' responses to cope with water-limited conditions have been extensively described based on cork-rings width and, more recently, on cork-rings density, in dendroecological studies. However, so far, tree functional attributes and physiological strategies, namely photosynthetic metabolism adjustments affecting cork formation, have never been addressed and/or integrated on these previous cork-rings-based studies. In this study, we address the relation between carbon and oxygen stable isotopes of cork rings and precipitation and temperature, in two distinct locations of southwestern Portugal-the (wetter) Tagus basin peneplain and the (drier) Grândola mountains. We aimed at assessing whether the two climatic factors affect cork-ring isotopic composition under contrasting conditions of water availability, and, therefore, if carbon and oxygen signatures in cork can reflect tree functional (physiological and structural) responses to stressful conditions, which might be aggravated by climate change. Our results indicate differences between the study areas. At the drier site, the stronger statistically significant negative cork δ 13C correlations were found with mean temperature, whereas strong positive cork δ 18O correlations were fewer and found only with precipitation. Moreover, at the wetter site, cork rings are enriched in 18O and depleted in 13C, indicating, respectively, shallow groundwater as the water source for physiological processes related with biosynthesis of non-photosynthetic secondary tissues, such as suberin, and a weak stomatal regulation under high water availability, consistent with non-existent water availability constrains. In contrast, at the drier site, trees use water from deeper ground layers, depleted in 18O, and strongly regulate stomatal conductance under water stress, thus reducing photosynthetic carbon uptake and probably relying on stored carbon reserves for cork ring formation. These results suggest that although stable isotopes signatures in cork rings are not proxies for net growth, they may be (fairly) robust indicators of trees' physiological and structural adjustments to climate and environmental changes in Mediterranean environments.

Novel <i>DNM1L</i> variants impair mitochondrial dynamics through divergent mechanisms.

Imbalances in mitochondrial and peroxisomal dynamics are associated with a spectrum of human neurological disorders. Mitochondrial and peroxisomal fission both involve dynamin-related protein 1 (DRP1) oligomerisation and membrane constriction, although the precise biophysical mechanisms by which distinct DRP1 variants affect the assembly and activity of different DRP1 domains remains largely unexplored. We analysed four unreported de novo heterozygous variants in the dynamin-1-like gene <i>DNM1L</i>, affecting different highly conserved DRP1 domains, leading to developmental delay, seizures, hypotonia, and/or rare cardiac complications in infancy. Single-nucleotide DRP1 stalk domain variants were found to correlate with more severe clinical phenotypes, with in vitro recombinant human DRP1 mutants demonstrating greater impairments in protein oligomerisation, DRP1-peroxisomal recruitment, and both mitochondrial and peroxisomal hyperfusion compared to GTPase or GTPase-effector domain variants. Importantly, we identified a novel mechanism of pathogenesis, where a p.Arg710Gly variant uncouples DRP1 assembly from assembly-stimulated GTP hydrolysis, providing mechanistic insight into how assembly-state information is transmitted to the GTPase domain. Together, these data reveal that discrete, pathological <i>DNM1L</i> variants impair mitochondrial network maintenance by divergent mechanisms.

OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy.

Mitochondrial stress triggers a response in the cell's mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we characterize a family with myopathy caused by a dominant p.G58R mutation in the mitochondrial protein CHCHD10. To understand the disease etiology, we developed a knockin (KI) mouse model and found that mutant CHCHD10 aggregated in affected tissues, applying a toxic protein stress to the inner mitochondrial membrane. Unexpectedly, the survival of CHCHD10-KI mice depended on a protective stress response mediated by the mitochondrial metalloendopeptidase OMA1. The OMA1 stress response acted both locally within mitochondria, causing mitochondrial fragmentation, and signaled outside the mitochondria, activating the integrated stress response through cleavage of DAP3-binding cell death enhancer 1 (DELE1). We additionally identified an isoform switch in the terminal complex of the electron transport chain as a component of this response. Our results demonstrate that OMA1 was critical for neonatal survival conditionally in the setting of inner mitochondrial membrane stress, coordinating local and global stress responses to reshape the mitochondrial network and proteome.

Biomarkers of systemic treatment response in people with psoriasis: a scoping review.

BACKGROUND: Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. OBJECTIVES: To perform a scoping review to identify and catalogue candidate biomarkers of systemic treatment response in psoriasis for the translational research community. METHODS: A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with systemic treatment response. The main outcomes were any measure of systemic treatment efficacy or safety. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise and mapped to relevant cellular and molecular pathways. RESULTS: Of 71 included studies (67 studying effectiveness outcomes and eight safety outcomes; four studied both), most reported genomic or proteomic biomarkers associated with response to biologics (48 studies). Methodological or reporting limitations frequently compromised the interpretation of findings, including inadequate control for key covariates, lack of adjustment for multiple testing, and selective outcome reporting. We identified candidate biomarkers of efficacy to tumour necrosis factor inhibitors [variation in CARD14, CDKAL1, IL1B, IL12B and IL17RA loci, and lipopolysaccharide-induced phosphorylation of nuclear factor (NF)-κB in type 2 dendritic cells] and ustekinumab (HLA-C*06:02 and variation in an IL1B locus). None were supported by sufficient evidence for clinical use without further validation studies. Candidate biomarkers were found to be involved in the immune cellular crosstalk implicated in psoriasis pathogenesis, most notably antigen presentation, T helper (Th)17 cell differentiation, positive regulation of NF-κB, and Th17 cell activation. CONCLUSIONS: This comprehensive catalogue provides a key resource for researchers and reveals a diverse range of biomarker types and outcomes in the included studies. The candidate biomarkers identified require further evaluation in methodologically robust studies to establish potential clinical utility. Future studies should aim to address the common methodological limitations highlighted in this review to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. What does this study add? This review provides a comprehensive catalogue of investigated biomarkers of systemic treatment response in psoriasis. A diverse range of biomarker types and outcomes was found in the included studies, serving as a key resource for the translational research community.

Biomarkers of disease progression in people with psoriasis: a scoping review.

BACKGROUND: Identification of those at risk of more severe psoriasis and/or associated morbidities offers opportunity for early intervention, reduced disease burden and more cost-effective healthcare. Prognostic biomarkers of disease progression have thus been the focus of intense research, but none are part of routine practice. OBJECTIVES: To identify and catalogue candidate biomarkers of disease progression in psoriasis for the translational research community. METHODS: A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with disease progression. The main outcomes were any measure of skin severity or any prespecified psoriasis comorbidity. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (longitudinal design and/or use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise, and mapped to relevant cellular and molecular pathways. RESULTS: Of 181 included studies, most investigated genomic or proteomic biomarkers associated with disease severity (n = 145) or psoriatic arthritis (n = 30). Methodological and reporting limitations compromised interpretation of findings, most notably a lack of longitudinal studies, and inadequate control for key prognostic factors. The following candidate biomarkers with future potential utility were identified for predicting disease severity: LCE3D, interleukin (IL)23R, IL23A, NFKBIL1 loci, HLA-C*06:02 (genomic), IL-17A, IgG aHDL, GlycA, I-FABP and kallikrein 8 (proteomic), tyramine (metabolomic); psoriatic arthritis: HLA-C*06:02, HLA-B*27, HLA-B*38, HLA-B*08, and variation at the IL23R and IL13 loci (genomic); IL-17A, CXCL10, Mac-2 binding protein, integrin b5, matrix metalloproteinase-3 and macrophage-colony stimulating factor (proteomic) and tyramine and mucic acid (metabolomic); and type 2 diabetes mellitus: variation in IL12B and IL23R loci (genomic). No biomarkers were supported by sufficient evidence for clinical use without further validation. CONCLUSIONS: This review provides a comprehensive catalogue of investigated biomarkers of disease progression in psoriasis. Future studies must address the common methodological limitations identified herein to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? The current treatment paradigm in psoriasis is reactive. There is a need to develop effective risk-stratified management approaches that can proactively attenuate the substantial burden of disease. Prognostic biomarkers of disease progression have therefore been the focus of intense research. What does this study add? This review is the first to scope, collate and catalogue research investigating biomarkers of disease progression in psoriasis. The review identifies potentially promising candidate biomarkers for further investigation and highlights common important limitations that should be considered when designing and conducting future studies in this area.

Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease.

Mitochondrial disorders are clinically and genetically heterogeneous, with variants in mitochondrial or nuclear genes leading to varied clinical phenotypes. TAMM41 encodes a mitochondrial protein with cytidine diphosphate-diacylglycerol synthase activity: an essential early step in the biosynthesis of phosphatidylglycerol and cardiolipin. Cardiolipin is a mitochondria-specific phospholipid that is important for many mitochondrial processes. We report three unrelated individuals with mitochondrial disease that share clinical features, including lethargy at birth, hypotonia, developmental delay, myopathy, and ptosis. Whole exome and genome sequencing identified compound heterozygous variants in TAMM41 in each proband. Western blot analysis in fibroblasts showed a mild oxidative phosphorylation (OXPHOS) defect in only one of the three affected individuals. In skeletal muscle samples, however, there was severe loss of subunits of complexes I-IV and a decrease in fully assembled OXPHOS complexes I-V in two subjects as well as decreased TAMM41 protein levels. Similar to the tissue-specific observations on OXPHOS, cardiolipin levels were unchanged in subject fibroblasts but significantly decreased in the skeletal muscle of affected individuals. To assess the functional impact of the TAMM41 missense variants, the equivalent mutations were modeled in yeast. All three mutants failed to rescue the growth defect of the Δtam41 strains on non-fermentable (respiratory) medium compared with wild-type TAM41, confirming the pathogenicity of the variants. We establish that TAMM41 is an additional gene involved in mitochondrial phospholipid biosynthesis and modification and that its deficiency results in a mitochondrial disorder, though unlike families with pathogenic AGK (Sengers syndrome) and TAFAZZIN (Barth syndrome) variants, there was no evidence of cardiomyopathy.

Differences in Clinical Features and Comorbid Burden between HLA-C∗06:02 Carrier Groups in >9,000 People with Psoriasis.

The identification of robust endotypes-disease subgroups of clinical relevance-is fundamental to stratified medicine. We hypothesized that HLA-C∗06:02 status, the major genetic determinant of psoriasis, defines a psoriasis endotype of clinical relevance. Using two United Kingdom-based cross-sectional datasets-an observational severe-psoriasis study (Biomarkers of Systemic Treatment Outcomes in Psoriasis; n = 3,767) and a large population-based bioresource (UK Biobank, including n = 5,519 individuals with psoriasis)-we compared demographic, environmental, and clinical variables of interest in HLA-C∗06:02-positive (one or two copies of the HLA-C∗06:02 allele) with those in HLA-C∗06:02‒negative (no copies) individuals of European ancestry. We used multivariable regression analyses to account for mediation effects established a priori. We confirm previous observations that HLA-C∗06:02-positive status is associated with earlier age of psoriasis onset and extend findings to reveal an association with disease expressivity in females (Biomarkers of Systemic Treatment Outcomes in Psoriasis: P = 2.7 × 10-14, UK Biobank: P = 1.0 × 10-8). We also show HLA-C∗06:02-negative status to be associated with characteristic clinical features (large plaque disease, OR for HLA-C∗06:02 = 0.73, P = 7.4 × 10-4; nail involvement, OR = 0.70, P = 2.4 × 10-6); higher central adiposity (Biomarkers of Systemic Treatment Outcomes in Psoriasis: waist circumference difference of 2.0 cm, P = 8.4 × 10-4; UK Biobank: waist circumference difference of 1.4 cm, P = 1.5 × 10-4), especially in women; and a higher prevalence of other cardiometabolic comorbidities. These findings extend the clinical phenotype delineated by HLA-C∗06:02 and highlight its potential as an important biomarker to consider in future multimarker stratified medicine approaches.