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Journal of Cell Science Mar 2023The primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport...
The primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport in the primary cilium result in ciliopathies, a group of genetic disorders that commonly lead to the malformation of organs such as the kidney, liver and eyes and skeletal dysplasias. The motor proteins dynein-2 and kinesin-2 mediate retrograde and anterograde transport, respectively, in the cilium. WDR34 (also known as DYNC2I2), a dynein-2 intermediate chain, is required for the maintenance of cilia function. Here, we investigated WDR34 mutations identified in Jeune syndrome, short-rib polydactyly syndrome and asphyxiating thoracic dysplasia patients. There is a poor correlation between genotype and phenotype in these cases, making diagnosis and treatment highly complex. We set out to define the biological impacts on cilia formation and function of WDR34 mutations by stably expressing the mutant proteins in WDR34-knockout cells. WDR34 mutations led to different spectrums of phenotypes. Quantitative proteomics demonstrated changes in dynein-2 assembly, whereas initiation and extension of the axoneme, localization of intraflagellar transport complex-B proteins, transition zone integrity and Hedgehog signalling were also affected.
Topics: Humans; Dyneins; Carrier Proteins; Hedgehog Proteins; Ellis-Van Creveld Syndrome; Cilia; Mutation
PubMed: 36268591
DOI: 10.1242/jcs.260073 -
Journal of Medical Case Reports Nov 2021Over-the-counter medication overdose is a difficult diagnostic challenge for many physicians as common drug screening assays cannot detect these substances. We present a...
BACKGROUND
Over-the-counter medication overdose is a difficult diagnostic challenge for many physicians as common drug screening assays cannot detect these substances. We present a case of acute psychosis, serotonin syndrome, and anticholinergic overdose-like properties in the setting of Coricidin HBP Cough & Cold tablets, known by their street name Triple-C. This is the first case report we are aware of involving a patient presenting with these symptoms and requiring critical-care-level support.
CASE PRESENTATION
A 31-year-old African American female with a past medical history of anxiety, childhood asthma, previous methamphetamine abuse, and coronavirus disease 2019 infection in August 2020 was brought to the emergency department by the local police department with altered mental status. Initial blood work, including extended drug screens, were unremarkable for a definitive diagnosis. This patient required critical-care-level support and high sedation because of her symptoms. Collateral history revealed the patient regularly consumed Triple-C daily for the 6 weeks prior to admission. A trial off sedation was attempted after 24 hours with no complications. The patient admitted to regular Triple-C consumption and auditory hallucinations since adolescence. She was discharged safely after 48 hours back into the community. She was lost to follow-up with psychiatry and internal medicine; however, she was evaluated in the emergency room 1 month later with a similar psychiatric presentation.
CONCLUSION
Overdose of Triple-C should be kept in the differential diagnosis of patients presenting with a triad of psychosis, serotonin syndrome, and anticholinergic overdose, in the setting of unknown substance ingestion.
Topics: Adolescent; Adult; COVID-19; Child; Drug Overdose; Female; Humans; Psychotic Disorders; SARS-CoV-2; Serotonin Syndrome
PubMed: 34732250
DOI: 10.1186/s13256-021-03163-z -
Genetics in Medicine : Official Journal... Jan 2021We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We also sought to determine if primary care providers (PCPs) and caregivers are satisfied with this personalized online health tool.
METHODS
In a national, randomized controlled trial of 230 caregivers who had children or dependents with DS without access to a DS specialist, 117 were randomized to receive DSC2U and 113 to receive usual care. The primary outcome was adherence to five health evaluations indicated by national guidelines for DS. DSC2U is completed electronically, in all mobile settings, by caregivers at home. The outputs-personalized checklists-are used during annual wellness visits with the patient's PCP.
RESULTS
A total of 213 participants completed a 7-month follow-up evaluation. In the intention-to-treat analysis, the intervention group had a 1.6-fold increase in the number of indicated evaluations that were recommended by the primary care provider or completed compared with controls. Both caregivers and PCPs reported high levels of satisfaction with DSC2U.
CONCLUSIONS
DSC2U improved adherence to the national DS health-care guidelines with a novel modality that was highly valued by both caregivers and PCPs.
Topics: Caregivers; Child; Down Syndrome; Health Personnel; Humans; Personal Satisfaction
PubMed: 32879436
DOI: 10.1038/s41436-020-00952-7 -
Disease Models & Mechanisms Jun 2022Heterozygous mutations in SNRPB, an essential core component of the five small ribonucleoprotein particles of the spliceosome, are responsible for cerebrocostomandibular...
Heterozygous mutations in SNRPB, an essential core component of the five small ribonucleoprotein particles of the spliceosome, are responsible for cerebrocostomandibular syndrome (CCMS). We show that Snrpb heterozygous mouse embryos arrest shortly after implantation. Additionally, heterozygous deletion of Snrpb in the developing brain and neural crest cells models craniofacial malformations found in CCMS, and results in death shortly after birth. RNAseq analysis of mutant heads prior to morphological defects revealed increased exon skipping and intron retention in association with increased 5' splice site strength. We found increased exon skipping in negative regulators of the P53 pathway, along with increased levels of nuclear P53 and P53 target genes. However, removing Trp53 in Snrpb heterozygous mutant neural crest cells did not completely rescue craniofacial development. We also found a small but significant increase in exon skipping of several transcripts required for head and midface development, including Smad2 and Rere. Furthermore, mutant embryos exhibited ectopic or missing expression of Fgf8 and Shh, which are required to coordinate face and brain development. Thus, we propose that mis-splicing of transcripts that regulate P53 activity and craniofacial-specific genes contributes to craniofacial malformations. This article has an associated First Person interview with the first author of the paper.
Topics: Animals; Craniofacial Abnormalities; Humans; Intellectual Disability; Mice; Micrognathism; Morphogenesis; Neural Crest; Ribs; Tumor Suppressor Protein p53; snRNP Core Proteins
PubMed: 35593225
DOI: 10.1242/dmm.049544 -
EMBO Molecular Medicine Sep 2016Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission. Mitochondrial...
Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission. Mitochondrial fusion is orchestrated by conserved GTPases MFN1/2 and OPA1, a process coordinated in yeast by Ugo1, a mitochondrial metabolite carrier family protein. We uncovered a homozygous missense mutation in SLC25A46, the mammalian orthologue of Ugo1, in a subject with Leigh syndrome. SLC25A46 is an integral outer membrane protein that interacts with MFN2, OPA1, and the mitochondrial contact site and cristae organizing system (MICOS) complex. The subject mutation destabilizes the protein, leading to mitochondrial hyperfusion, alterations in endoplasmic reticulum (ER) morphology, impaired cellular respiration, and premature cellular senescence. The MICOS complex is disrupted in subject fibroblasts, resulting in strikingly abnormal mitochondrial architecture, with markedly shortened cristae. SLC25A46 also interacts with the ER membrane protein complex EMC, and phospholipid composition is altered in subject mitochondria. These results show that SLC25A46 plays a role in a mitochondrial/ER pathway that facilitates lipid transfer, and link altered mitochondrial dynamics to early-onset neurodegenerative disease and cell fate decisions.
Topics: Cells, Cultured; Endoplasmic Reticulum; Female; Homeostasis; Humans; Leigh Disease; Lipid Metabolism; Mitochondria; Mitochondrial Proteins; Mutation, Missense; Phosphate Transport Proteins
PubMed: 27390132
DOI: 10.15252/emmm.201506159 -
Cell Death & Disease Jan 2021Mutations of WD40 repeat domain 60 (WDR60) have been identified in short-rib polydactyly syndromes (SRPS I-V), a group of lethal congenital disorders characterized by...
Mutations of WD40 repeat domain 60 (WDR60) have been identified in short-rib polydactyly syndromes (SRPS I-V), a group of lethal congenital disorders characterized by short ribs, polydactyly, and a range of extraskeletal phenotypes. However, the underlying mechanism is still unclear. Here, we report that WDR60 is essential for embryonic development and plays a critical role in the multipolar-bipolar transition and migration of newborn neurons during brain development. Mechanically, we found that WDR60 was located at the microtubule-organizing center to control microtubule organization and possibly, the trafficking of cellular components. Importantly, the migration defect caused by Wdr60 knockdown could be rescued by the stable form of α-Tubulin, α-Tubulin (an acetylation-mimicking mutant). These findings identified a non-cilia function of WDR60 and provided insight into its biological function, as well as the pathogenesis of WDR60 deficiency associated with SRPS.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Movement; Female; Humans; Mice; Neurogenesis; Neurons; Rats; Short Rib-Polydactyly Syndrome
PubMed: 33436552
DOI: 10.1038/s41419-020-03363-3 -
Cell Cycle (Georgetown, Tex.) 2015Short-rib polydactyly syndromes (SRPS) arise from mutations in genes involved in retrograde intraflagellar transport (IFT) and basal body homeostasis, which are critical...
Short-rib polydactyly syndromes (SRPS) arise from mutations in genes involved in retrograde intraflagellar transport (IFT) and basal body homeostasis, which are critical for cilia assembly and function. Recently, mutations in WDR34 or WDR60 (candidate dynein intermediate chains) were identified in SRPS. We have identified and characterized Tctex1d2, which associates with Wdr34, Wdr60 and other dynein complex 1 and 2 subunits. Tctex1d2 and Wdr60 localize to the base of the cilium and their depletion causes defects in ciliogenesis. We propose that Tctex1d2 is a novel dynein light chain important for trafficking to the cilium and potentially retrograde IFT and is a new molecular link to understanding SRPS pathology.
Topics: Adaptor Proteins, Signal Transducing; Carrier Proteins; Cilia; Cytoskeletal Proteins; Dyneins; HEK293 Cells; HeLa Cells; Humans; Microtubule-Organizing Center; Mutation; Protein Transport; Short Rib-Polydactyly Syndrome
PubMed: 25830415
DOI: 10.4161/15384101.2014.985066 -
Nature Jan 2017XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the...
XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.
Topics: Adenosine Diphosphate Ribose; Alleles; Animals; Apraxias; Ataxia; Axons; Cerebellar Ataxia; Cerebellum; Chromatin; Cogan Syndrome; DNA Breaks, Single-Stranded; DNA Repair; DNA Repair Enzymes; DNA-Binding Proteins; Female; Humans; Interneurons; Male; Mice; Mutation; Pedigree; Phenotype; Phosphotransferases (Alcohol Group Acceptor); Poly (ADP-Ribose) Polymerase-1; X-ray Repair Cross Complementing Protein 1
PubMed: 28002403
DOI: 10.1038/nature20790 -
Journal of Applied Research in... Jul 2021People with Down syndrome (DS) have a unique medical profile which may impact views of health. We aimed to explore the use of global health measures in DS.
PURPOSE
People with Down syndrome (DS) have a unique medical profile which may impact views of health. We aimed to explore the use of global health measures in DS.
METHODS
Prospective survey in the Mass General Hospital Down Syndrome Program (MGH DSP) from December 2018 to July 2019 with Patient Reported Outcomes Measurement Information System (PROMIS)® instruments of global health. Analyses included use of scoring manuals, descriptive statistics and dependent samples t test.
RESULTS
Seventeen adolescents, 48 adults with DS and 88 caregivers returned surveys; 137 were complete. Incomplete responses and notes showed limitations of the instruments in this population. Global health T-scores did not differ from the available comparative standardized scores to these measures from PROMIS® reference population (p > 0.05).
CONCLUSIONS
In the MGH DSP, pilot global health instruments were completed by some adults with DS and caregivers, with some limitations and scores similar to the PROMIS® reference population.
Topics: Adolescent; Adult; Down Syndrome; Global Health; Humans; Intellectual Disability; Prospective Studies; Quality of Life; Surveys and Questionnaires
PubMed: 33759305
DOI: 10.1111/jar.12866 -
Kardiologia Polska 2015According to the current guidelines, atrioventricular (DDD) pacing is superior to atrial pacing (AAI) in the treatment of sick sinus syndrome (SSS).
BACKGROUND
According to the current guidelines, atrioventricular (DDD) pacing is superior to atrial pacing (AAI) in the treatment of sick sinus syndrome (SSS).
AIM
To compare outcomes of AAI and DDD pacing in patients with SSS during long-term follow-up.
METHODS
We studied 809 patients, including 86 patients in the AAI group (57 women, mean age 65 ± 15 years) and 723 patients in the DDD group (406 women, mean age 71.5 ± 10 years). Evaluation of outcomes of AAI and DDD pacing in SSS was based on the analysis of medical records of patients who underwent pacemaker implantation.
RESULTS
Average duration of follow-up was 52 ± 25 months. In the AAI group, 63 of 86 patients remained without intervention. In the DDD group, 661 of 723 patients did not require surgical intervention. Overall, 105 patients died, including 13 in the AAI group and 92 in the DDD group (p = 0.4516). In the AAI group, a high degree atrioventricular block occurred on average after 46.3 ± 8.8 months and its incidence was estimated at 0.85% per year. Atrial fibrillation (AF) developed in 8 patients in the AAI group and 81 patients in the DDD group (p = 0.23). Among aetiological factors of an increased risk of developing AF, only the presence of tachycardia-bradycardia syndrome (hazard ratio [HR] 11.31) and the absence of antiarrhythmic therapy (HR 4.23) significantly increased the risk of AF. Urgent reoperation was needed in 23 patients in the AAI group and 62 patients in the DDD group (p < 0.01). Log-rank test analysis showed a significant effect of the development of AF on the risk of reoperation in this group (p = 0.0420). Lead-related complications were noted in 6 patients in the AAI group and 49 patients in the DDD group (p = 0.94). After 45 months, the risk of reoperation in the AAI group increased significantly due to a need for ventricular lead implantation.
CONCLUSIONS
1. Atrial stimulation is safe in SSS but it may be associated with an increased risk of ventricular lead implantation if atrioventricular block or persistent AF with slow ventricular rate develops. 2. DDD and AAI groups did not differ significantly in terms of survival, development of persistent AF, and lead-related complications. 3. Tachycardia-bradycardia syndrome and the lack of antiarrhythmic treatment with beta-blocker and amiodarone increased the risk of persistent AF during long-term follow-up. 4. A higher rate of reoperations in patients with AAI systems, related mainly to development of persistent AF, especially after the fourth year of follow-up, may justify DDD system implantation in SSS.
Topics: Aged; Aged, 80 and over; Cardiac Pacing, Artificial; Female; Follow-Up Studies; Humans; Male; Middle Aged; Sick Sinus Syndrome; Treatment Outcome
PubMed: 25001847
DOI: 10.5603/KP.a2014.0148