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Kaufman oculocerebrofacial syndrome (KOS) is a severe autosomal recessive disorder characterized by intellectual disability, developmental delays, microcephaly, and characteristic dysmorphisms. Biallelic mutations of UBE3B, encoding for a ubiquitin ligase E3B are causative for KOS. In this report, we characterize neuronal functions of its murine ortholog Ube3b and show that Ube3b regulates dendritic branching in a cell-autonomous manner. Moreover, Ube3b knockout (KO) neurons exhibit increased density and aberrant morphology of dendritic spines, altered synaptic physiology, and changes in hippocampal circuit activity. Dorsal forebrain-specific Ube3b KO animals show impaired spatial learning, altered social interactions, and repetitive behaviors. We further demonstrate that Ube3b ubiquitinates the catalytic γ-subunit of calcineurin, Ppp3cc, the overexpression of which phenocopies Ube3b loss with regard to dendritic spine density. This work provides insights into the molecular pathologies underlying intellectual disability-like phenotypes in a genetically engineered mouse model.

Objectives Due to upcoming gene‐specific therapy approaches for ALS patients, understanding familial and sporadic ALS genetics is becoming increasingly important. In this study, we wanted to investigate underlying genetic causes for an SALS patient. Methods We performed ALS gene panel sequencing and subsequent segregation analysis in the family. Results Genetic studies suggest that a proportion of SALS cases has an oligogenic origin due to the combination of low‐effect size mutations in several ALS genes. Maximally three mutations in different ALS disease genes have been described in isolated ALS patients. Here, we report for the first time the co‐occurrence of rare nonsynonymous variants in four known ALS genes in a SALS patient (c.859G > A/p.Gly287Ser in TARDBP, c.304G > T/p.Glu102* in NEK1, c.3446C > A/p.Gly1149Val in ERBB4, and c.1015C > T/p.Arg339Trp in VEGFA). All four variants were unique for the patient, whereas up to three of these variants were detected in the unaffected family members, all older than the patient. Discussion Our study suggests that SALS can be caused by the additive or synergistic action of low‐effect size mutations. Broader use of gene panel analysis or whole exome/genome sequencing may reveal a potentially treatable oligogenic causation in a higher percentage of SALS than previously thought. We identified a sporadic ALS patient with four rare variants in four different genes linked to ALS causation. The older family members carrying combinations of these two or three variants were unaffected and did not have any neurodegenerative disease. This study expands our understanding of oligogenic inheritance in SALS.

Primary cilia (PC) are microtubule-based protrusions of the cell membrane transducing molecular signals during brain development. Here, we report that PC are required for maintenance of Substantia nigra (SN) dopaminergic (DA) neurons highly vulnerable in Parkinson’s disease (PD). Targeted blockage of ciliogenesis in differentiated DA neurons impaired striato-nigral integrity in adult mice. The relative number of SN DA neurons displaying a typical auto-inhibition of spontaneous activity in response to dopamine was elevated under control metabolic conditions, but not under metabolic stress. Strikingly, in the absence of PC, the remaining SN DA neurons were less vulnerable to the PD neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP). Our data indicate conserved PC-dependent neuroadaptive responses to DA lesions in the striatum. Moreover, PC control the integrity and dopamine response of a subtype of SN DA neurons. These results reinforce the critical role of PC as sensors of metabolic stress in PD and other disorders of the dopamine system.

Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis–ptosis–intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B -related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello–Carey syndrome as well as the patient reported to have a “new” syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B -associated phenotypes, including forms that can mimick Toriello–Carey syndrome, and suggest the single designation “Kaufman oculocerebrofacial syndrome”.

The ELR(+)-CXCL chemokines have been described typically as potent chemoattractants and activators of neutrophils during the acute phase of inflammation. Their role in atherosclerosis, a chronic inflammatory vascular disease, has been largely unexplored. Using a mouse model of atherosclerosis, we found that CXCL5 expression was upregulated during disease progression, both locally and systemically, but was not associated with neutrophil infiltration. Unexpectedly, inhibition of CXCL5 was not beneficial but rather induced a significant macrophage foam cell accumulation in murine atherosclerotic plaques. Additionally, we demonstrated that CXCL5 modulated macrophage activation, increased expression of the cholesterol efflux regulatory protein ABCA1, and enhanced cholesterol efflux activity in macrophages. These findings reveal a protective role for CXCL5, in the context of atherosclerosis, centered on the regulation of macrophage foam cell formation.

Light is an important environmental cue that affects physiology and development of Neurospora crassa. The light-sensing transcription factor (TF) WCC, which consists of the GATA-family TFs WC1 and WC2, is required for light-dependent transcription. SUB1, another GATA-family TF, is not a photoreceptor but has also been implicated in light-inducible gene expression. To assess regulation and organization of the network of light-inducible genes, we analyzed the roles of WCC and SUB1 in light-induced transcription and nucleosome remodeling. We show that SUB1 co-regulates a fraction of light-inducible genes together with the WCC. WCC induces nucleosome eviction at its binding sites. Chromatin remodeling is facilitated by SUB1 but SUB1 cannot activate light-inducible genes in the absence of WCC. We identified FF7, a TF with a putative O-acetyl transferase domain, as an interaction partner of SUB1 and show their cooperation in regulation of a fraction of light-inducible and a much larger number of non light-inducible genes. Our data suggest that WCC acts as a general switch for light-induced chromatin remodeling and gene expression. SUB1 and FF7 synergistically determine the extent of light-induction of target genes in common with WCC but have in addition a role in transcription regulation beyond light-induced gene expression.

Mutations in FUS and TBK1 often cause aggressive early-onset amyotrophic lateral sclerosis (ALS) or a late-onset ALS and/or frontotemporal dementia (FTD) phenotype, respectively. Co-occurrence of mutations in two or more Mendelian ALS/FTD genes has been repeatedly reported. However, little is known how two pathogenic ALS/FTD mutations in the same patient interact to shape the final phenotype. We screened 28 ALS patients with a known FUS mutation by whole-exome sequencing and targeted evaluation for mutations in other known ALS genes followed by genotype–phenotype correlation analysis of FUS/TBK1 double-mutant patients. We report on new and summarize previously published FUS and TBK1 double-mutant ALS/FTD patients and their families. We found that, within a family, mutations in FUS cause ALS while TBK1 single mutations are observed in FTD patients. FUS/TBK1 double mutations manifested as ALS and without a manifest difference regarding age at onset and disease duration when compared to FUS single-mutant individuals. In conclusion, TBK1 and FUS variants do not seem to interact in a simple additive way. Rather, the phenotype of FUS/TBK1 double-mutant patients appears to be dominated by the FUS mutation.

Background/Objectives: Acute decompensated heart failure (ADHF) presents a significant clinical challenge characterized by frequent hospitalizations, high mortality rates, and substantial healthcare costs. The united index of hemoglobin, albumin, lymphocytes and platelets (HALP) is a new indicator that reflects systemic inflammation and nutritional status. This study aimed to investigate the prognostic utility of the HALP score and hematological parameters in predicting short-term mortality among ADHF patients admitted to the coronary care unit (CCU). Methods: This investigation adopts a retrospective observational design, encompassing a cohort of patients with ADHF who were followed in the CCU at our medical institution between January 2019 and April 2024. Results: The cohort of 227 individuals was dichotomized into two subsets based on the presence or absence of short-term mortality in the hospital, resulting in 163 (71.8%) and 64 (28.2%) individuals in the survivor and exitus groups, respectively. Age was significantly higher in the exitus group (p-value = 0.004). Hemoglobin, lymphocyte count, platelet count, albumin, and HALP score were significantly higher in the survivor group (all p-values < 0.001). No significant difference was observed between the groups in terms of gender, diabetes mellitus (DM), coronary artery disease (CAD), or ejection fraction (EF), although hypertension (HT) prevalence was significantly higher in the exitus group (p-value = 0.038). ROC analysis demonstrated that hemoglobin, lymphocyte, albumin, and HALP score had significant discriminative power, with albumin showing the highest AUC (0.814). Conclusions: In conclusion, the HALP score and hematological parameters represent valuable prognostic feature for short-term mortality prediction in ADHF patients admitted to the CCU. These findings underscore the importance of early risk stratification and targeted interventions guided by comprehensive biomarker assessments in optimizing patient outcomes.

Background: Heart failure (HF) causes high morbidity and mortality worldwide. The prevalence of HF with preserved ejection fraction (HFpEF) is increasing compared with HF with reduced ejection fraction (HFrEF). Patients with HFpEF are a patient group with a high rate of hospitalization despite medical treatment. Early diagnosis is very important in this group of patients, and early treatment can improve their prognosis. Although electrocardiographic (ECG) findings have been adequately studied in patients with HFrEF, there are not enough studies on these parameters in patients with HFpEF. There are very few studies in the literature, especially on gender-specific changes. The current research aims to compare gender-specific ECG parameters in patients with HFpEF based on the implications of artificial intelligence (AI). Methods: A total of 118 patients participated in the study, of which 66 (56%) were women with HFpEF and 52 (44%) were men with HFpEF. Demographic, echocardiographic, and electrocardiographic characteristics of the patients were analyzed to compare gender-specific ECG parameters in patients with HFpEF. The AI approach combined with machine learning approaches (gradient boosting machine, k-nearest neighbors, logistic regression, random forest, and support vector machines) was applied for distinguishing male patients with HFpEF from female patients with HFpEF. Results: After determining the parameters (demographic, echocardiographic, and electrocardiographic) to distinguish male patients with HFpEF from female patients with HFpEF, machine learning methods were applied, and among these methods, the random forest model achieved an average accuracy of 84.7%. The random forest algorithm results showed that smoking, P-wave dispersion, P-wave amplitude, T-end P/(PQ*Age), Cornell product, and P-wave duration were the most influential parameters for distinguishing male patients with HFpEF from female patients with HFpEF. Conclusions: The proposed model serves as a valuable tool for physicians, facilitating the diagnosis, treatment, and follow-up for distinguishing male patients with HFpEF from female patients with HFpEF. Analyzing readily accessible electrocardiographic parameters empowers medical professionals to make informed decisions and provide enhanced care to a wide range of individuals.

Background Amelogenesis imperfecta (AI) is a highly heterogeneous group of hereditary developmental abnormalities which mainly affects the dental enamel during tooth development in terms of its thickness, structure, and composition. It appears both in syndromic as well as non-syndromic forms. In the affected individuals, the enamel is usually thin, soft, rough, brittle, pitted, chipped, and abraded, having reduced functional ability and aesthetics. It leads to severe complications in the patient, like early tooth loss, severe discomfort, pain, dental caries, chewing difficulties, and discoloration of teeth from yellow to yellowish-brown or creamy type. The study aimed to identify the disease-causing variant in a consanguineous family. Methods We recruited a consanguineous Pashtun family of Pakistani origin. Exome sequencing analysis was followed by Sanger sequencing to identify the pathogenic variant in this family. Results Clinical analysis revealed hypomaturation AI having generalized yellow-brown or creamy type of discoloration in affected members. We identified a novel nonsense sequence variant c.1192C > T (p.Gln398*) in exon-12 of SLC24A4 by using exome sequencing. Later, its co-segregation within the family was confirmed by Sanger sequencing. The human gene mutation database (HGMD, 2019) has a record of five pathogenic variants in SLC24A4 , causing AI phenotype. Conclusion This nonsense sequence variant c.1192C > T (p.Gln398*) is the sixth disease-causing variant in SLC24A4 , which extends its mutation spectrum and confirms the role of this gene in the morphogenesis of human tooth enamel. The identified variant highlights the critical role of SLC24A4 in causing a rare AI type in humans.