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Gene Expression Patterns : GEP Sep 2018Cilia are essential for sensory and motile functions across species. In humans, ciliary dysfunction causes "ciliopathies", which show severe developmental abnormalities...
Cilia are essential for sensory and motile functions across species. In humans, ciliary dysfunction causes "ciliopathies", which show severe developmental abnormalities in various tissues. Several missense mutations in intestinal cell kinase (ICK) gene lead to endocrine-cerebro-osteodysplasia syndrome or short rib-polydactyly syndrome, lethal recessive developmental ciliopathies. We and others previously reported that Ick-deficient mice exhibit neonatal lethality with developmental defects. Mechanistically, Ick regulates intraflagellar transport and cilia length at ciliary tips. Although Ick plays important roles during mammalian development, roles of Ick at the adult stage are poorly understood. In the current study, we investigated the Ick gene expression in adult mouse tissues. RT-PCR analysis showed that Ick is ubiquitously expressed, with enrichment in the retina, brain, lung, intestine, and reproductive system. In the adult brain, we found that Ick expression is enriched in the walls of the lateral ventricle, in the rostral migratory stream of the olfactory bulb, and in the subgranular zone of the hippocampal dentate gyrus by in situ hybridization analysis. We also observed that Ick staining pattern is similar to pachytene spermatocyte to spermatid markers in the mature testis and to an intestinal stem cell marker in the adult small intestine. These results suggest that Ick is expressed in proliferating regions in the adult mouse brain, testis, and intestine.
Topics: Animals; Brain; Cell Proliferation; Cells, Cultured; Gene Expression Regulation, Developmental; Intestinal Mucosa; Intestines; Male; Mice; Protein Serine-Threonine Kinases; Signal Transduction; Stem Cells; Testis
PubMed: 29635032
DOI: 10.1016/j.gep.2018.04.005 -
Molecular Genetics & Genomic Medicine Dec 2020Skeletal ciliopathies are a group of clinically and genetically heterogeneous disorders with the spectrum of severity spanning from relatively mild to prenatally lethal....
BACKGROUND
Skeletal ciliopathies are a group of clinically and genetically heterogeneous disorders with the spectrum of severity spanning from relatively mild to prenatally lethal. The aim of our study was to identify pathogenic mutations in a Chinese family with two siblings presenting a Short-rib polydactyly syndrome (SRPS)-like phenotype.
METHOD
Karyotyping and NGS-based CNVseq were performed. Obtaining the negative results in karyotyping and CNVseq, whole-exome sequencing (WES) using genomic DNA (gDNA) extracted from the umbilical cord blood of the first fetus was carried out, followed by bioinformation analysis. The candidate pathogenic variants were confirmed by Sanger sequencing in the family.
RESULTS
No chromosomal abnormalities and pathogenic copy number variations (CNVs) were detected in the affected fetus with SRPS-like phenotype. WES analysis identified two novel compound heterozygous variants in DYNC2LI1, c.358G>T (p.Pro120Ser; NM_001193464), and c.928A>T (p.Lys310Ter; NM_ 001193464). Bioinformatics analysis suggested that c.358G>T (p.Pro120Ser) was likely pathogenic and c.928A>T (p.Lys310Ter) was pathogenic. Sanger sequencing of the two variants in family reveal that c.358G>T was from paternal origin and c.928A>T was from maternal origin, and the second affected fetus had the same compound heterozygous variants in DYNC2LI1. Definitive diagnosis of short-rib thoracic dysplasia 15 with polydactyly (SRTD15) was made in the family.
CONCLUSION
Our results expand the mutational spectrum of DYNC2LI1 in severe skeletal ciliopathies. WES facilitates the accurate prenatal diagnosis of fetal skeletal ciliopathy, and provides helpful information for genetic counseling.
Topics: Adult; Ciliopathies; Cytoplasmic Dyneins; Female; Fetus; Heterozygote; Humans; Male; Point Mutation; Pregnancy; Short Rib-Polydactyly Syndrome; Ultrasonography, Prenatal; Whole Genome Sequencing
PubMed: 33030252
DOI: 10.1002/mgg3.1524 -
BMC Medical Genetics Apr 2015Mutations in CCBE1 have been found to be responsible for a subset of families with autosomal recessive Hennekam syndrome. Hennekam syndrome is defined as the combination... (Review)
Review
BACKGROUND
Mutations in CCBE1 have been found to be responsible for a subset of families with autosomal recessive Hennekam syndrome. Hennekam syndrome is defined as the combination of generalized lymphatic dysplasia (ie. lymphedema and lymphangiectasia), variable intellectual disability and characteristic dysmorphic features. The patient we describe here has a lymphatic dysplasia without intellectual disability or dysmorphism caused by mutation in CCBE1, highlighting the phenotypic variability that can be seen with abnormalities in this gene.
CASE PRESENTATION
Our patient is a 5 week old child of Pakistani descent who presented to our center with generalized edema, ascites, and hypoalbuminemia. She was diagnosed with a protein losing enteropathy secondary to segmental primary intestinal lymphangiectasia. As the generalized edema resolved, it became clear that she had mild persistent lymphedema in her hands and feet. No other abnormalities were noted on examination and development was unremarkable at 27 months of age. Given the suspected genetic etiology and the consanguinity in the family, we used a combination of SNP genotyping and exome sequencing to identify the underlying cause of her disease. We identified several large stretches of homozygosity in the patient that allowed us to sort the variants found in the patient's exome to identify p.C98W in CCBE1 as the likely pathogenic variant.
CONCLUSIONS
CCBE1 mutation analysis should be considered in all patients with unexplained lymphatic dysplasia even without the other features of classic Hennekam syndrome.
Topics: Calcium-Binding Proteins; Consanguinity; Craniofacial Abnormalities; DNA Mutational Analysis; Female; Genital Diseases, Male; Genotype; Humans; Hypoalbuminemia; Infant; Lymphangiectasis, Intestinal; Lymphatic System; Lymphedema; Pakistan; Polydactyly; Polymorphism, Single Nucleotide; Protein-Losing Enteropathies; Tumor Suppressor Proteins
PubMed: 25925991
DOI: 10.1186/s12881-015-0175-0 -
Brain Sciences Jul 2020Since the end of 2019, the whole world has been struggling with the pandemic of the new Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Available evidence...
Since the end of 2019, the whole world has been struggling with the pandemic of the new Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Available evidence suggests that pain is a common symptom during Coronavirus Disease 2019 (COVID-19). According to the World Health Organization, many patients suffer from muscle pain (myalgia) and/or joint pain (arthralgia), sore throat and headache. The exact mechanisms of headache and myalgia during viral infection are still unknown. Moreover, many patients with respiratory failure get admitted to the intensive care unit (ICU) for ventilatory support. Pain in ICU patients can be associated with viral disease itself (myalgia, arthralgia, peripheral neuropathies), may be caused by continuous pain and discomfort associated with ICU treatment, intermittent procedural pain and chronic pain present before admission to the ICU. Undertreatment of pain, especially when sedation and neuromuscular blocking agents are used, prone positioning during mechanical ventilation or extracorporeal membrane oxygenation (ECMO) may trigger delirium and cause peripheral neuropathies. This narrative review summarizes current knowledge regarding challenges associated with pain assessment and management in COVID-19 patients. A structured prospective evaluation should be undertaken to analyze the probability, severity, sources and adequate treatment of pain in patients with COVID-19 infection.
PubMed: 32698378
DOI: 10.3390/brainsci10070465 -
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 -
American Journal of Medical Genetics.... Oct 2020Short-rib polydactyly syndromes are a heterogeneous group of disorders characterized by narrow thorax with short ribs, polydactyly and often other visceral and skeletal...
Short-rib polydactyly syndromes are a heterogeneous group of disorders characterized by narrow thorax with short ribs, polydactyly and often other visceral and skeletal malformations. To date there have only been six reported patients with homozygous and compound heterozygous variants in IFT81, causing a short-rib thoracic dysplasia, with, or without, polydactyly (SRTD19: OMIM 617895). IFT81 is a protein integral to the core of the intraflagellar transport complex B (IFT-B), which is involved in anterograde transport in the cilium. We describe the case of a male infant with compound heterozygous variants in IFT81, who presented with short long bones, a narrow thorax, polydactyly, and multiple malformations. Three novel clinical features are reported including complete situs inversus, micropenis, and rectal atresia, which have not previously been associated with variants in IFT81. We reviewed the literature and identified the most consistent clinical features associated with this rare ciliopathy syndrome. We postulate that dolichocephaly and sagittal craniosynostosis may be associated with this condition, and provide a clue to considering IFT81 as the causative gene when deciphering complex ciliopathies.
Topics: Cilia; Ciliopathies; Craniosynostoses; Homozygote; Humans; Infant, Newborn; Male; Muscle Proteins; Mutation; Phenotype; Short Rib-Polydactyly Syndrome
PubMed: 32783357
DOI: 10.1002/ajmg.a.61781 -
Medicine Feb 2020KIAA0586 variants have been associated to short-rib thoracic dysplasia, an autosomal recessive skeletal ciliopathy characterized by a narrow thorax, short limbs, and...
INTRODUCTION
KIAA0586 variants have been associated to short-rib thoracic dysplasia, an autosomal recessive skeletal ciliopathy characterized by a narrow thorax, short limbs, and radiological skeletal abnormalities.
PATIENT CONCERNS
Patients 1 and 2 were two Roma Gypsy siblings presenting thoracic dysplasia and a combination of oral cavity anomalies.
DIAGNOSIS
A custom NGS gene panel, including genes associated to skeletal ciliopathies, identified the homozygous KIAA0586 splicing variant c.1815G>A (p.Gln605Gln) in both siblings, confirming the clinical diagnosis of short-rib-polydactyly.
INTERVENTION
Patients were transferred to neonatal intensive care unit and received life-support treatment.
OUTCOMES
Patients 1 and 2 died after few hours and 1 month of birth, respectively, because of respiratory failure related with the disease.
CONCLUSION
We report two patients affected by short-rib polydactyly syndrome and overlapping phenotype with oral-facial-digital syndrome associated with the c.1815G>A variant in KIAA0586, suggesting a quite peculiar genotype-phenotype correlation.
Topics: Cell Cycle Proteins; Ciliopathies; Humans; Infant, Newborn; Italy; Male; Orofaciodigital Syndromes; Phenotype; Roma; Short Rib-Polydactyly Syndrome; Siblings
PubMed: 32080096
DOI: 10.1097/MD.0000000000019169 -
Nature Communications Jun 2015The short rib polydactyly syndromes (SRPSs) are a heterogeneous group of autosomal recessive, perinatal lethal skeletal disorders characterized primarily by short,...
The short rib polydactyly syndromes (SRPSs) are a heterogeneous group of autosomal recessive, perinatal lethal skeletal disorders characterized primarily by short, horizontal ribs, short limbs and polydactyly. Mutations in several genes affecting intraflagellar transport (IFT) cause SRPS but they do not account for all cases. Here we identify an additional SRPS gene and further unravel the functional basis for IFT. We perform whole-exome sequencing and identify mutations in a new disease-producing gene, cytoplasmic dynein-2 light intermediate chain 1, DYNC2LI1, segregating with disease in three families. Using primary fibroblasts, we show that DYNC2LI1 is essential for dynein-2 complex stability and that mutations in DYNC2LI1 result in variable length, including hyperelongated, cilia, Hedgehog pathway impairment and ciliary IFT accumulations. The findings in this study expand our understanding of SRPS locus heterogeneity and demonstrate the importance of DYNC2LI1 in dynein-2 complex stability, cilium function, Hedgehog regulation and skeletogenesis.
Topics: Biological Transport; Cilia; Cytoplasmic Dyneins; Cytoskeleton; Female; Fibroblasts; Flagella; Hedgehog Proteins; Humans; Male; Mutation; Pedigree; Short Rib-Polydactyly Syndrome
PubMed: 26077881
DOI: 10.1038/ncomms8092 -
European Journal of Human Genetics :... Jul 2016Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria,...
Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband's de novo DNM1L variant, NM_012062.4:c.1085G>A; NP_036192.2:p.(Gly362Asp), falls within the middle (oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy.
Topics: Cells, Cultured; Child; Developmental Disabilities; Drug Resistant Epilepsy; Dynamins; Exome; Fibroblasts; GTP Phosphohydrolases; Humans; Male; Microtubule-Associated Proteins; Mitochondria, Muscle; Mitochondrial Dynamics; Mitochondrial Proteins; Muscle, Skeletal; Mutation, Missense; Syndrome
PubMed: 26604000
DOI: 10.1038/ejhg.2015.243 -
Nucleic Acids Research Dec 2023Molnupiravir (EIDD-2801) is an antiviral that received approval for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Treatment of...
Molnupiravir (EIDD-2801) is an antiviral that received approval for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Treatment of bacteria or cell lines with the active form of molnupiravir, β-d-N4-hydroxycytidine (NHC, or EIDD-1931), induces mutations in DNA. Yet these results contrast in vivo genotoxicity studies conducted during registration of the drug. Using a CRISPR screen, we found that inactivating the pyrimidine salvage pathway component uridine-cytidine kinase 2 (Uck2) renders cells more tolerant of NHC. Short-term exposure to NHC increased the mutation rate in a mouse myeloid cell line, with most mutations being T:A to C:G transitions. Inactivating Uck2 impaired the mutagenic activity of NHC, whereas over-expression of Uck2 enhanced mutagenesis. UCK2 is upregulated in many cancers and cell lines. Our results suggest differences in ribonucleoside metabolism contribute to the variable mutagenicity of NHC observed in cancer cell lines and primary tissues.
Topics: Animals; Mice; Antiviral Agents; Cytidine; Mutagenesis; Mutagens; RNA, Viral; Uridine Kinase
PubMed: 37953355
DOI: 10.1093/nar/gkad1002