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Molecular Vision 2021Cytoplasmic dyneins (dynein-1 and dynein-2) transport cargo toward the minus end of microtubules and thus, are termed the "retrograde" cellular motor. Dynein-1 cargo may... (Review)
Review
Cytoplasmic dyneins (dynein-1 and dynein-2) transport cargo toward the minus end of microtubules and thus, are termed the "retrograde" cellular motor. Dynein-1 cargo may include nuclei, mitochondria, membrane vesicles, lysosomes, phagosomes, and other organelles. For example, dynein-1 works in the cell body of eukaryotes to move cargo toward the microtubule minus end and positions the Golgi complex. Dynein-1 also participates in the movement of chromosomes and the positioning of mitotic spindles during cell division. In contrast, dynein-2 is present almost exclusively within cilia where it participates in retrograde intraflagellar transport (IFT) along the axoneme to return kinesin-2 subunits, BBSome, and IFT particles to the cell body. Cytoplasmic dyneins are hefty 1.5 MDa complexes comprised of dimers of heavy, intermediate, light intermediate, and light chains. Missense mutations of human are associated with malformations of cortical development (MCD) or spinal muscular atrophy with lower extremity predominance (SMA-LED). Missense mutations in are causative of short-rib polydactyly syndrome type III and nonsyndromic retinitis pigmentosa. We review mutations of the two dynein heavy chains and their effect on postnatal retina development and discuss consequences of deletion of in the mouse retina.
Topics: Animals; Cytoplasmic Dyneins; Gene Expression; Humans; Mice; Mutation; Photoreceptor Cells, Vertebrate; Retinal Diseases
PubMed: 34526758
DOI: No ID Found -
Protein Science : a Publication of the... Nov 2021Phosphatidylserine (PS) synthase 1 (PSS1) of mammalian cells is a multiple membrane-spanning protein of the endoplasmic reticulum (ER) and regulated by inhibition with...
Phosphatidylserine (PS) synthase 1 (PSS1) of mammalian cells is a multiple membrane-spanning protein of the endoplasmic reticulum (ER) and regulated by inhibition with the product PS. Alanine-scanning mutagenesis of PSS1 has revealed eight amino acid residues as those crucial for its activity and six as those important for its regulation. Furthermore, three missense mutations in the human PSS1 gene, which lead to regulatory dysfunctions of PSS1 and are causative of Lenz-Majewski syndrome, have been identified. In this study, we investigated the membrane topology of PSS1 by means of epitope insertion and immunofluorescence. According to a 10-transmembrane segment model supported by topology analysis of PSS1, all the 8 amino acid residues crucial for the enzyme activity were localized to the luminal side of the lipid bilayer or the lumen of the ER, whereas all the 9 amino acid residues involved in the enzyme regulation were localized to the cytosol or the cytoplasmic side of the lipid bilayer of the ER. This localization of the functional amino acid residues suggests that PSS1 is regulated by inhibition with PS in the cytoplasmic leaflet of the ER membrane and synthesizes PS at the luminal leaflet.
Topics: Endoplasmic Reticulum; HeLa Cells; Humans; Intracellular Membranes; Lipid Bilayers; Nitrogenous Group Transferases
PubMed: 34516042
DOI: 10.1002/pro.4182 -
Cells Jul 2021Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary... (Review)
Review
Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary structures or components results in a large heterogeneous group of disorders in mammals, termed ciliopathies. The majority of human ciliopathy cases are caused by malfunction of the ciliary dynein motor activity, powering retrograde intraflagellar transport (enabled by the cytoplasmic dynein-2 complex) or axonemal movement (axonemal dynein complexes). Despite a partially shared evolutionary developmental path and shared ciliary localization, the cytoplasmic dynein-2 and axonemal dynein functions are markedly different: while cytoplasmic dynein-2 complex dysfunction results in an ultra-rare syndromal skeleto-renal phenotype with a high lethality, axonemal dynein dysfunction is associated with a motile cilia dysfunction disorder, primary ciliary dyskinesia (PCD) or Kartagener syndrome, causing recurrent airway infection, degenerative lung disease, laterality defects, and infertility. In this review, we provide an overview of ciliary dynein complex compositions, their functions, clinical disease hallmarks of ciliary dynein disorders, presumed underlying pathomechanisms, and novel developments in the field.
Topics: Animals; Axonemal Dyneins; Cilia; Ciliopathies; Cytoplasmic Dyneins; Humans; Kartagener Syndrome; Polymorphism, Genetic; Short Rib-Polydactyly Syndrome
PubMed: 34440654
DOI: 10.3390/cells10081885 -
Molecular Medicine Reports Jun 2021Short rib‑polydactyly syndrome type III (SRPS3) is a lethal perinatal skeletal disorder consisting of polydactyly and multi‑system organ abnormalities. To further...
Short rib‑polydactyly syndrome type III (SRPS3) is a lethal perinatal skeletal disorder consisting of polydactyly and multi‑system organ abnormalities. To further assess the pathogenicity of two pairs of compound heterozygotes and to search for novel molecular etiology, X‑rays and hematoxylin and eosin staining were conducted in three cases: Two retrospective samples and a newly identified patient with SRPS3. In addition, next‑generation sequencing was used to evaluate a fetus with SRPS3. Typical radiological features of the three cases included a long, narrow thorax with short ribs, shortened long bones, spurs at the metaphysis of the long bones and congenital bowing of the femurs. The present study also observed atypical histopathological changes, together with the absence of proliferation and abundance of retaining cartilage in the primary spongiosum. In addition, two novel compound heterozygous variants were identified in the dynein cytoplasmic 2 heavy chain 1 () gene of the fetus: NM_001080463.1, c.6591_6593delTGG (chr11:103055738‑103055740); NM_001080463.1, c.7883T>C (chr11:103070000). The findings of the present study provided further confirmation of the pathogenicity of two compound heterozygous variants in two retrospective samples and identified novel compound heterozygous variants. These findings may improve our knowledge of the histopathological and radiological changes in patients with SRPS3 and the relative effects of variants. The findings of the present study may facilitate the clinical and molecular diagnosis of SRPS3.
Topics: Adult; Cytoplasmic Dyneins; Female; Fetus; High-Throughput Nucleotide Sequencing; Humans; Pedigree; Radiography; Retrospective Studies; Short Rib-Polydactyly Syndrome
PubMed: 33846808
DOI: 10.3892/mmr.2021.12065 -
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 -
Clinical Genetics Jun 2021
Topics: Cytoplasmic Dyneins; Fetus; Humans; Mutation; Ribs; Short Rib-Polydactyly Syndrome
PubMed: 33694158
DOI: 10.1111/cge.13953 -
Clinical Genetics Jun 2021Recurrent hydatidiform moles (RHMs) are human pregnancies with abnormal embryonic development and hyperproliferating trophoblast. Biallelic mutations in NLRP7 and...
Recurrent hydatidiform moles (RHMs) are human pregnancies with abnormal embryonic development and hyperproliferating trophoblast. Biallelic mutations in NLRP7 and KHDC3L, members of the subcortical maternal complex (SCMC), explain the etiology of RHMs in only 60% of patients. Here we report the identification of seven functional variants in a recessive state in three SCMC members, five in NLRP7, one in NLRP5, and one in PADI6. In NLRP5, we report the first patient with RHMs and biallelic mutations. In PADI6, the patient had four molar pregnancies, two of which had fetuses with various abnormalities including placental mesenchymal dysplasia and intra-uterine growth restriction, which are features of Beckwith-Wiedemann syndrome and Silver Russell syndrome, respectively. Our findings corroborate recent studies and highlight the common oocyte origin of all these conditions and the continuous spectrum of abnormalities associated with deficiencies in the SCMC genes.
Topics: Adaptor Proteins, Signal Transducing; Autoantigens; Beckwith-Wiedemann Syndrome; Female; Humans; Hydatidiform Mole; Mitochondrial Proteins; Mutation; Neoplasm Recurrence, Local; Nuclear Proteins; Oocytes; Placenta; Pregnancy; Protein-Arginine Deiminase Type 6; Uterine Neoplasms
PubMed: 33583041
DOI: 10.1111/cge.13941 -
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 -
Health Physics Apr 2021A suite of software tools has been developed for dose estimation (BAT, WinFRAT) and prediction of acute health effects (WinFRAT, H-Module) using clinical symptoms and/or...
A suite of software tools has been developed for dose estimation (BAT, WinFRAT) and prediction of acute health effects (WinFRAT, H-Module) using clinical symptoms and/or changes in blood cell counts. We constructed a database of 191 ARS cases using the METREPOL (n = 167) and the SEARCH-database (n = 24). The cases ranged from unexposed (RC0), to mild (RC1), moderate (RC2), severe (RC3), and lethal ARS (RC4). From 2015-2019, radiobiology students and participants of two NATO meetings predicted clinical outcomes (RC, H-ARS, and hospitalization) based on clinical symptoms. We evaluated the prediction outcomes using the same input datasets with a total of 32 teams and 94 participants. We found that: (1) unexposed (RC0) and mildly exposed individuals (RC1) could not be discriminated; (2) the severity of RC2 and RC3 were systematically overestimated, but almost all lethal cases (RC4) were correctly predicted; (3) introducing a prior education component for non-physicians significantly increased the correct predictions of RC, ARS, and hospitalization by around 10% (p<0.005) with a threefold reduction in variance and a halving of the evaluation time per case; (4) correct outcome prediction was independent of the software tools used; and (5) comparing the dose estimates generated by the teams with H-ARS severity reflected known limitations of dose alone as a surrogate for H-ARS severity. We found inexperienced personnel can use software tools to make accurate diagnostic and treatment recommendations with up to 98% accuracy. Educational training improved the quality of decision making and enabled participants lacking a medical background to perform comparably to experts.
Topics: Acute Radiation Syndrome; Databases, Factual; Hospitalization; Humans; Radiobiology; Software
PubMed: 33315652
DOI: 10.1097/HP.0000000000001353 -
FASEB Journal : Official Publication of... Jan 2021Enzymatic control of lipid homeostasis in the cell is a vital element in the complex organization of life. Phosphatidylserine (PS) is an essential anionic phospholipid... (Review)
Review
Enzymatic control of lipid homeostasis in the cell is a vital element in the complex organization of life. Phosphatidylserine (PS) is an essential anionic phospholipid of cell membranes, and conducts numerous roles for their structural and functional integrity. In mammalian cells, two distinct enzymes phosphatidylserine synthases-1 (PSS1) and -2 (PSS2) in the mitochondria-associated membrane (MAM) in the ER perform de novo synthesis of PS. It is based on base-exchange reactions of the preexisting dominant phospholipids phosphatidylcholine (PC) and phosphatidylethanolamine (PE). While PSS2 specifically catalyzes the reaction "PE → PS," whether or not PSS1 is responsible for the same reaction along with the reaction "PC → PS" remains unsettled despite its fundamental impact on the major stoichiometry. We propose here that a key but the only report that appeared to have put scientists on hold for decades in answering to this issue may be viewed consistently with other available research reports; PSS1 utilizes the two dominant phospholipid classes at a similar intrinsic rate. In this review, we discuss the issue in view of the current information for the enzyme machineries, membrane structure and dynamics, intracellular network of lipid transport, and PS synthesis in health and disease. Resolution of the pending issue is thus critical in advancing our understanding of roles of the essential anionic lipid in biology, health, and disease.
Topics: Animals; Homeostasis; Humans; Lipid Metabolism; Mitochondrial Membranes; Nitrogenous Group Transferases; Phosphatidylethanolamines; Phosphatidylserines
PubMed: 33205488
DOI: 10.1096/fj.202001802R