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.
Remodeling of the left ventricle (LV) after myocardial infarction (MI) is a process of infarct enlargement. Despite the relevance of the inflammatory response and healing process in LV remodeling ...after MI, the mechanisms that begin and govern these processes remain unknown. Based on the important information highlighted in different studies, the current research aims to investigate potential biomarkers for left ventricular remodeling after acute MI based on the interpretation of the explainable artificial intelligence (XAI). The project research from which the public dataset was obtained was designed in an experimental type. A cohort study involving 66 patients with coronary heart disease and 34 healthy community controls provided the platelet samples for the current research, which used available omics data on those samples. For discovering significant mechanistic connections between metabolites and glycans, the metabolomics and glycomics datasets were analyzed using biostatistics/metabolomics and explainable artificial intelligence techniques. Metabolomics data of 100 patients (AMI=66; Control=34) including 75 males and 25 females were evaluated in this study. As a result of experimental omics analyses, 102 metabolite levels of the patients were obtained. When FC values were examined, creatinine and dl-pipecolic acid levels were 0.50 and 0.55-fold down-regulated and glutamine, myoinositol, and cytosine levels were 1.34, 1.33, and 1.53-fold up-regulated in the AMI group compared to the control group. Findings of metabolomics data and XAI analyses revealed that five lipid metabolites may be used as potential predictors of AMI.
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.
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.
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”.
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.
The Uric acid/Albumin ratio (UAR) has recently been identified as a prominent marker in cardiovascular diseases. In this study, we aimed to reveal the effect of UAR on coronary collateral circulation ...(CCC) in patients with stable coronary artery disease (CAD) patients by comparing it with conventional inflammation-based markers.
In this study, 415 consecutive patients who underwent coronary angiography for stable angina pectoris and were found to have chronic total occlusion in at least one coronary artery were retrospectively included. The study population was divided into two groups as good CCC (Rentrop 2-3) and poor CCC (Rentrop 0-1) according to the Rentrop classification, and the groups were compared in terms of UAR and other traditional inflammation-based markers.
In the poor CCC group, C-reactive protein/albumin ratio (CAR), monocyte/high-density lipoprotein cholesterol ratio (MHR), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), systemic immune-inflammation index (SII) and UAR were found to be significantly high (
< .05, for all). UAR negatively correlated with rentrop classification (r = -0.383,
< .001). In multivariate regression analysis, MHR, NLR, SII and UAR were determined as independent predictors for poor CCC (
< .05, for all). The ability of UAR to predict poor CCC was superior to uric acid and albumin alone (
< .0001, for both). In addition, UAR was found to be superior to other inflammation-based markers in predicting poor CCC (
< .005, for all).
UAR was identified as a strong and independent predictor of CCC. In this context, UAR may be a useful biomarker in the risk prediction of patients with stable CAD.
Mutations in the human kinesin family member 5A (KIF5A) gene were recently identified as a genetic cause of amyotrophic lateral sclerosis (ALS). Several KIF5A ALS variants cause exon 27 skipping and ...are predicted to produce motor proteins with an altered C‐terminal tail (referred to as ΔExon27). However, the underlying pathogenic mechanism is still unknown. Here, we confirm the expression of KIF5A mutant proteins in patient iPSC‐derived motor neurons. We perform a comprehensive analysis of ΔExon27 at the single‐molecule, cellular, and organism levels. Our results show that ΔExon27 is prone to form cytoplasmic aggregates and is neurotoxic. The mutation relieves motor autoinhibition and increases motor self‐association, leading to drastically enhanced processivity on microtubules. Finally, ectopic expression of ΔExon27 in Drosophila melanogaster causes wing defects, motor impairment, paralysis, and premature death. Our results suggest gain‐of‐function as an underlying disease mechanism in KIF5A‐associated ALS.
Synopsis
The ALS‐associated KIF5A ΔExon27 mutation drives the disease via a gain‐of‐function mechanism caused by constitutive activation and increased motor association and aggregation of mutant KIF5A.
KIF5A ΔExon27 is aggregation‐prone and is neurotoxic.
KIF5A ΔExon27 displays relieved autoinhibition, increased motor self‐association, and enhanced processivity on microtubules.
ALS patient iPSC‐derived motor neurons express mutant KIF5A proteins.
Ectopic expression of KIF5A ΔExon27 in Drosophila leads to abnormal wings, motor deficits, paralysis, and premature death.
The ALS‐associated KIF5A ΔExon27 mutation drives the disease via a gain‐of‐function mechanism caused by constitutive activation and increased motor association and aggregation of mutant KIF5A.
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.
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