ABSTRACT
Over the past decades, daughter designs, including genotyped sires and their genotyped daughters, have been used as an approach to identify QTL related to economic traits. The aim of this study was to identify genomic regions inherited by Gir sire families and genes associated with number of viable oocytes (VO), total number of oocytes (TO), and number of embryos (EMBR) based on a daughter design approach. In total, 15 Gir sire families were selected. The number of daughters per family ranged from 26 to 395, which were genotyped with different SNP panels and imputed to the Illumina BovineHD BeadChip (777K) and had phenotypes for oocyte and embryo production. Daughters had phenotypic data for VO, TO, and EMBR. The search for QTL was performed through GWAS based on GBLUP. The QTL were found for each trait among and within families based on the top 10 genomic windows with the greatest genetic variance. For EMBR, genomic windows identified among families were located on BTA4, BTA5, BTA6, BTA7, BTA8, BTA13, BTA16, and BTA17, and they were most frequent on BTA7 within families. For VO, genomic windows were located on BTA2, BTA4, BTA5, BTA7, BTA17, BTA21, BTA22, BTA23, and BTA27 among families, being most frequent on BTA8 within families. For TO, the top 10 genomic windows were identified on BTA2, BTA4, BTA5, BTA7, BTA17, BTA21, BTA22, BTA26, and BTA27, being most frequent on BTA7 and BTA8 within families. Considering all results, the greatest number of genomic windows was found on BTA7, where the VCAN, XRCC4, TRNAC-ACA, HAPLN1, and EDIL3 genes were identified in the common regions. In conclusion, 15 Gir sire families with 26 to 395 daughters per family with phenotypes for oocyte and embryo production helped to identify the inheritance of several genomic regions, especially on BTA7, where the EDIL3, HAPLN1, and VCAN candidate genes were associated with number of oocytes and embryos in Gir cattle families.
Subject(s)
Genotype , Oocytes , Phenotype , Animals , Cattle/genetics , Female , Quantitative Trait Loci , Male , Genome , Genomics , Breeding , Genome-Wide Association Study/veterinary , Polymorphism, Single NucleotideABSTRACT
The DNA sensor cGAS (cyclic GMP-AMP synthase) and its adaptor protein STING (Stimulator of Interferon Genes) detect the presence of cytosolic DNA as a sign of infection or damage. In cancer cells, this pathway can be activated through persistent DNA damage and chromosomal instability, which results in the formation of micronuclei and the exposure of DNA fragments to the cytosol. DNA damage from radio- or chemotherapy can further activate DNA sensing responses, which may occur in the cancer cells themselves or in stromal and immune cells in the tumour microenvironment (TME). cGAS-STING signalling results in the production of type I interferons, which have been linked to immune cell infiltration in 'hot' tumours that are susceptible to immunosurveillance and immunotherapy approaches. However, recent research has highlighted the complex nature of STING signalling, with tumours having developed mechanisms to evade and hijack this signalling pathway for their own benefit. In this mini-review we will explore how cGAS-STING signalling in different cells in the TME can promote both anti-tumour and pro-tumour responses. This includes the role of type I interferons and the second messenger cGAMP in the TME, and the influence of STING signalling on local immune cell populations. We examine how alternative signalling cascades downstream of STING can promote chronic interferon signalling, the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of inflammatory cytokines, which can have pro-tumour functions. An in-depth understanding of DNA sensing in different cell contexts will be required to harness the anti-tumour functions of STING signalling.
Subject(s)
Interferon Type I , Neoplasms , Humans , Immunity, Innate/genetics , DNA/metabolism , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolism , Interferon Type I/genetics , Interferon Type I/metabolism , Neoplasms/therapy , Tumor MicroenvironmentABSTRACT
INTRODUCTION: Persistent spinal pain syndrome (PSPS) or failed back surgery syndrome (FBSS) refers to new or persistent pain following spinal surgery for back or leg pain in a subset of patients. Spinal cord stimulation (SCS) is a neuromodulation technique that can be considered in patients with predominant leg pain refractory to conservative treatment. Patients with predominant low back pain benefit less from SCS. Another neuromodulation technique for treatment of chronic low back pain is subcutaneous stimulation or peripheral nerve field stimulation (PNFS). We investigated the effect of SCS with additional PNFS on pain and quality of life of patients with PSPS compared with that of SCS alone after 12 months. MATERIALS AND METHODS: This is a comparative study of patients with PSPS who responded to treatment with either SCS + PNFS or SCS only following a multicenter randomized clinical trial protocol. In total, 75 patients completed the 12-month follow-up: 21 in the SCS-only group and 54 in the SCS + PNFS group. Outcome measures were pain (visual analog scale), quality of life (36-Item Short Form Survey [SF-36]), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), overall health (EuroQol Five-Dimension [EQ-5D]), disability (Oswestry Disability Index [ODI]), and pain assessed by the McGill questionnaire. RESULTS: There were no significant differences in baseline characteristics between the two groups. Both groups showed a significant reduction in back and leg pain at 12 months compared with baseline measurements. No significant differences were found between the groups in effect on both primary (pain) and secondary parameters (SF-36, HADS, EQ-5D, ODI, and McGill pain). CONCLUSION: In a subgroup of patients with chronic back and leg pain, SCS alone provided similar long-term pain relief and quality-of-life improvement as PNFS in addition to SCS. In patients with refractory low back pain not responding to SCS alone, adding PNFS should be recommended. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT01776749.
Subject(s)
Low Back Pain , Spinal Cord Stimulation , Humans , Back Pain/therapy , Back Pain/complications , Low Back Pain/therapy , Peripheral Nerves , Quality of Life , Spinal Cord Stimulation/methodsABSTRACT
We developed a fast and accurate polynomial based atmospheric correction (POLYAC) algorithm for hyperspectral radiometric measurements, which parameterizes the atmospheric path radiances using aerosol properties retrieved from co-located multi-wavelength multi-angle polarimeter (MAP) measurements. This algorithm has been applied to co-located spectrometer for planetary exploration (SPEX) airborne and research scanning polarimeter (RSP) measurements, where SPEX airborne was used as a proxy of hyperspectral radiometers, and RSP as the MAP. The hyperspectral remote sensing reflectance obtained from POLYAC is accurate when compared to Aerosol Robotic Network (AERONET), and Visible Infrared Imaging Radiometer Suite (VIIRS) ocean color products. POLYAC provides a robust alternative atmospheric correction algorithm for hyperspectral or multi-spectral radiometric measurements for scenes involving coastal oceans and/or absorbing aerosols, where traditional atmospheric correction algorithms are less reliable.
ABSTRACT
Anthropogenic aerosol emissions lead to an increase in the amount of cloud condensation nuclei and consequently an increase in cloud droplet number concentration and cloud albedo. The corresponding negative radiative forcing due to aerosol cloud interactions (RF[Formula: see text]) is one of the most uncertain radiative forcing terms as reported in the 5th Assessment Report of the Intergovernmental Panel on Climate Change (IPCC). Here we show that previous observation-based studies underestimate aerosol-cloud interactions because they used measurements of aerosol optical properties that are not directly related to cloud formation and are hampered by measurement uncertainties. We have overcome this problem by the use of new polarimetric satellite retrievals of the relevant aerosol properties (aerosol number, size, shape). The resulting estimate of RF[Formula: see text] = -1.14 Wm[Formula: see text] (range between -0.84 and -1.72 Wm[Formula: see text]) is more than a factor 2 stronger than the IPCC estimate that includes also other aerosol induced changes in cloud properties.
ABSTRACT
To improve our understanding of the complex role of aerosols in the climate system and on air quality, measurements are needed of optical and microphysical aerosol. From many studies, it has become evident that a satellite-based multiangle, multiwavelength polarimeter will be essential to provide such measurements. Here, high accuracy (â¼0.003) on the degree of linear polarization (DoLP) measurements is important to retrieve aerosol properties with an accuracy needed to advance our understanding of the aerosol effect on climate. SPEX airborne, a multiangle hyperspectral polarimeter, has been developed for observing and characterizing aerosols from NASA's high-altitude research aircraft ER-2. It delivers measurements of radiance and DoLP at visual wavelengths with a spectral resolution of 3 and 7-30 nm, respectively, for radiance and polarization, at nine fixed equidistant viewing angles from -56° to +56° oriented along the ground track, and a swath of 7° oriented across-track. SPEX airborne uses spectral polarization modulation to determine the state of linear polarization of scattered sunlight. This technique has been developed in the Netherlands and has been demonstrated with ground-based instruments. SPEX airborne serves as a demonstrator for a family of space-based SPEX instruments that have the ability to measure and characterize atmospheric aerosol by multiangle hyperspectral polarimetric imaging remotely from a satellite platform. SPEX airborne was calibrated radiometrically and polarimetrically using Jet Propulsion Laboratory (JPL) facilities including the Polarization Stage Generator-2 (PSG-2), which is designed for polarimetric calibration and validation of the Airborne Multiangle SpectroPolarimetric Imager (AirMSPI). Using the PSG-2, the accuracy of the SPEX airborne DoLP measurements in the laboratory setup is found to be 0.002-0.004. Radiometric calibration is realized with an estimated accuracy of 4%. In 2017, SPEX airborne took part in the "Aerosol Characterization from Polarimeters and Lidar" campaign on the ER-2 that included four polarimeters and two lidars. Polarization measurements of SPEX airborne and the coflying Research Scanning Polarimeter (RSP), recorded during the campaign, were compared and display root-mean-square (RMS) differences ranging from 0.004 (at 555 nm) up to 0.02 (at 410 nm). For radiance measurements, excellent agreement between SPEX airborne and RSP is obtained with an RMS difference of â¼4%. The lab- and flight-performance values for polarization are similar to those recently published for AirMSPI, where also an intercomparison with RSP was made using data from field campaigns in 2013. The intercomparison of radiometric and polarimetric data both display negligible bias. The in-flight comparison results provide verification of SPEX airborne's capability to deliver high-quality data.
ABSTRACT
There are few case reports of cases of carotid and aortic dissection related to the ergotamine abuse, but the cases that affect the coronary arteries is a very rare coronary. We present a patient of a 48-year-old female with an ST-segment elevation myocardial infarction attributable to chronic ergotamine use. The coronary angiography showed dissection of right coronary artery proximal.
Subject(s)
Acute Coronary Syndrome/chemically induced , Analgesics, Non-Narcotic/adverse effects , Ergotamine/adverse effects , ST Elevation Myocardial Infarction/chemically induced , Acute Coronary Syndrome/diagnostic imaging , Coronary Angiography , Electrocardiography , Female , Humans , Middle Aged , Migraine Disorders/drug therapy , ST Elevation Myocardial Infarction/diagnostic imagingABSTRACT
Anthropogenic methane emissions from China are likely greater than in any other country in the world. The largest fraction of China's anthropogenic emissions is attributable to coal mining, but these emissions may be changing; China enacted a suite of regulations for coal mine methane (CMM) drainage and utilization that came into full effect in 2010. Here, we use methane observations from the GOSAT satellite to evaluate recent trends in total anthropogenic and natural emissions from Asia with a particular focus on China. We find that emissions from China rose by 1.1 ± 0.4 Tg CH4 yr-1 from 2010 to 2015, culminating in total anthropogenic and natural emissions of 61.5 ± 2.7 Tg CH4 in 2015. The observed trend is consistent with pre-2010 trends and is largely attributable to coal mining. These results indicate that China's CMM regulations have had no discernible impact on the continued increase in Chinese methane emissions.
ABSTRACT
BACKGROUND: Blood lactate concentration is a marker of tissue perfusion and helps guide therapeutic interventions in critically ill horses. In both humans and dogs, administration of corticosteroids can increase blood lactate concentration, leading to type B hyperlactatemia. This effect could be a consequence of the impact of corticosteroids on glucose metabolism. OBJECTIVES: To investigate the effects of daily IM dexamethasone administration on blood lactate and glucose concentrations in horses. ANIMALS: Nine healthy adult horses. METHODS: A randomized, blinded, controlled, cross-over study design was used. Horses were randomly assigned to 1 of 2 groups, either receiving 0.05 mg/kg of dexamethasone IM or an equivalent volume of saline, daily for 7 days. Blood was collected to determine lactate and glucose concentrations at baseline, 2 hours after the daily injections and 24 hours after the last injection. RESULTS: Dexamethasone treatment had a statistically significant effect on lactate (P = .006) and glucose (P = .033) concentrations. The least squares mean lactate concentration was 0.93 mmol/L (95% CI: 0.87-0.99) in the dexamethasone group compared to 0.71 mmol/L (95% CI: 0.70-0.73) for the saline group. A positive relationship between blood lactate and glucose concentrations was identified, with a 0.07 mmol/L (95% CI: 0.05-0.09) increase in lactate concentration per unit increase in glucose (P < .0001) concentration. CONCLUSIONS AND CLINICAL IMPORTANCE: Dexamethasone induces statistically significant increases in blood lactate and glucose concentrations in healthy horses. Awareness of the potential for corticosteroids to induce type B hyperlactatemia might be important in the management of critically ill horses receiving dexamethasone.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Dexamethasone/pharmacology , Horses/blood , Lactic Acid/blood , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/blood , Anti-Inflammatory Agents/pharmacokinetics , Cross-Over Studies , Dexamethasone/administration & dosage , Dexamethasone/blood , Dexamethasone/pharmacokinetics , Female , Injections, Intramuscular/veterinary , Male , Single-Blind Method , Treatment OutcomeABSTRACT
OBJECTIVES: This study was designed to compare outcomes of the most common pediatric cardiac interventions from the time of implementation with the current era. BACKGROUND: Since the introduction of semilunar valve balloon dilation and device closure of the arterial duct and septal defects, development of interventional techniques and devices has been rapid. However, few studies have compared outcomes between those initial interventions and those in the current era. METHODS: Five validated common catheter-based therapies were chosen for analysis, including atrial and duct device closure, balloon dilation of the aortic and pulmonary valves, and native coarctation of the aorta. A retrospective review of the first and most recent 10 consecutive patients in each group was performed. RESULTS: There was a high mortality (30%) among neonates who underwent aortic valve (AV) dilation in the early era, but no mortality noted in other groups. In the early era, transcatheter atrial defect closure and AV dilations were associated with a low success rate (60% for both lesions) and a high complication rate (40% for atrial septal defect, 30% for AV dilations). Among the last 10 children, the atrial defect occlusion was successful in 100% without complications and AV dilations where successful in all children with a 30% complication rate (one major, two minor). CONCLUSIONS: A learning curve with device development plays a significant role in the evolution of transcatheter techniques. These data provide baseline estimates of success and may be used as a template in the future when new techniques are adapted into practice.
Subject(s)
Cardiac Catheterization , Cardiology , Heart Defects, Congenital/therapy , Pediatrics , Radiography, Interventional , Adolescent , Age Factors , Cardiac Catheterization/adverse effects , Cardiac Catheterization/history , Cardiac Catheterization/instrumentation , Cardiac Catheterization/mortality , Cardiac Catheterization/trends , Cardiology/history , Cardiology/trends , Child , Child, Preschool , Diffusion of Innovation , Disease-Free Survival , Heart Defects, Congenital/history , Heart Defects, Congenital/mortality , History, 20th Century , Humans , Infant , Infant, Newborn , Kaplan-Meier Estimate , Ontario , Pediatrics/history , Pediatrics/trends , Radiation Exposure , Radiography, Interventional/adverse effects , Radiography, Interventional/history , Radiography, Interventional/mortality , Radiography, Interventional/trends , Retrospective Studies , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
Three major clinical subgroups are usually distinguished in Mucopolysaccharidosis type I: Hurler (MPS IH, severe presentation), Hurler-Scheie (MPS IH/S, intermediate) and Scheie (MPS IS, mild). To facilitate treatment with hematopoietic stem-cell transplantation, early diagnosis is important for MPS IH patients. Although screening for MPS I in newborns would allow detection at an early age, it may be difficult to predict the phenotype on the basis of the genotype in these infants. Extra diagnostic tools are thus required. Based on the hypothesis that distinct MPS I phenotypes may result from differences in residual α-l-iduronidase (IDUA) activity, we modified the common IDUA assay using the substrate 4-methylumbelliferyl-α-l-iduronide to allow quantification of low IDUA activity in MPS I fibroblasts. Enzyme incubation was performed with high protein concentrations at different time points up to 8h. Mean residual IDUA activity was 0.18% (range 0-0.6) of the control value in MPS IH fibroblasts (n=5); against 0.27% (range 0.2-0.3) in MPS IH/S cells (n=3); and 0.79% (range 0.3-1.8) in MPS IS fibroblasts (n=5). These results suggest that residual IDUA activity and severity of the MPS I phenotype are correlated. Two MPS IS patients with rare (E276K/E276K) or indefinite (A327P/unknown) IDUA genotypes had residual IDUA activity in the MPS IS range, illustrating the usefulness of our approach. IDUA(E276K) was very unstable at 37°C, but more stable at 23°C, suggesting thermal instability. We conclude that this procedure for determining residual IDUA activity in fibroblasts of MPS I patients may be helpful to predict MPS I phenotype.
Subject(s)
Fibroblasts/enzymology , Hymecromone/analogs & derivatives , Iduronidase/metabolism , Mucopolysaccharidosis I/diagnosis , Cell Line , Early Diagnosis , Humans , Hymecromone/metabolism , Infant, Newborn , Mucopolysaccharidosis I/enzymology , Mucopolysaccharidosis I/metabolism , Mucopolysaccharidosis I/pathology , MutationABSTRACT
Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and laboratory findings. A group of biochemical genetics laboratory directors and clinicians involved in the diagnosis of MPS IVA, convened by BioMarin Pharmaceutical Inc., met to develop recommendations for diagnosis. The following conclusions were reached. Due to the wide variation and subtleties of radiographic findings, imaging of multiple body regions is recommended. Urinary glycosaminoglycan analysis is particularly problematic for MPS IVA and it is strongly recommended to proceed to enzyme activity testing even if urine appears normal when there is clinical suspicion of MPS IVA. Enzyme activity testing of GALNS is essential in diagnosing MPS IVA. Additional analyses to confirm sample integrity and rule out MPS IVB, multiple sulfatase deficiency, and mucolipidoses types II/III are critical as part of enzyme activity testing. Leukocytes or cultured dermal fibroblasts are strongly recommended for enzyme activity testing to confirm screening results. Molecular testing may also be used to confirm the diagnosis in many patients. However, two known or probable causative mutations may not be identified in all cases of MPS IVA. A diagnostic testing algorithm is presented which attempts to streamline this complex testing process.
Subject(s)
Glycosaminoglycans/urine , Mucopolysaccharidosis IV/diagnosis , Mucopolysaccharidosis IV/enzymology , Algorithms , Fibroblasts/enzymology , Humans , Leukocytes/enzymology , Mucolipidoses/diagnosis , Mucopolysaccharidosis IV/genetics , Mucopolysaccharidosis IV/urine , Multiple Sulfatase Deficiency Disease/diagnosis , Mutation , Pathology, Molecular/methodsABSTRACT
Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder caused by a deficiency of iduronate 2-sulfatase (IDS). Progressive, intralysosomal accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in almost all tissues leads to multi-organ involvement in affected males but to virtual absence of symptoms in heterozygote female carriers due to preferential inactivation of the mutant allele. Diagnosis of MPS II in males is based on IDS analysis in leukocytes, fibroblasts, plasma, or dried blood spots (DBS), whereas IDS activities may be within the normal range in heterozygote females. The advent of fluorometric and mass spectrometry methods for enzyme analysis in DBS has simplified the diagnostic approach for MPS II males. Molecular analysis of the IDS gene confirms the diagnosis of MPS II in males and is the only diagnostic test to confirm carrier status in females. This unit provides detailed analytical protocols for measurement of IDS activity in DBS and plasma using a fluorometric assay.
Subject(s)
Dried Blood Spot Testing/methods , Fluorometry/methods , Glycoproteins/blood , Mucopolysaccharidosis II/diagnosis , Dermatan Sulfate/metabolism , Female , Glycoproteins/deficiency , Glycoproteins/genetics , Heparitin Sulfate/metabolism , Humans , Lysosomes/pathology , Male , Mucopolysaccharidosis II/geneticsABSTRACT
Dried blood spot (DBS) methods are currently available for identification of a range of lysosomal storage disorders (LSDs). These disorders are generally characterized by a deficiency of activity of a lysosomal enzyme and by a broad spectrum of phenotypes. Diagnosis of LSD patients is often delayed, which is of particular concern as therapeutic outcomes (e.g. enzyme replacement therapy) are generally more favorable in early disease stages. Experts in the field of LSDs diagnostics and screening programs convened and reviewed experiences with the use of DBS methods, and discuss the diagnostic challenges, possible applications and quality programs in this paper. Given the easy sampling and shipping and stability of samples, DBS has evident advantages over other laboratory methods and can be particularly helpful in the early identification of affected LSD patients through neonatal screening, high-risk population screening or family screening.
Subject(s)
Dried Blood Spot Testing/methods , Dried Blood Spot Testing/trends , Lysosomal Storage Diseases/blood , Lysosomal Storage Diseases/diagnosis , Dried Blood Spot Testing/standards , Humans , Quality Control , Reference Standards , Research ReportABSTRACT
OBJECTIVE: Mucopolysaccharidosis (MPS) IIIA (Sanfilippo syndrome type A) is a lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. Information on the natural course of MPS IIIA is scarce, but is much needed in view of emerging therapies. METHODS: Clinical history and molecular defects of all 110 MPS IIIA patients identified by enzymatic studies in the Netherlands were collected and included in this study. RESULTS: First clinical signs, mainly consisting of delayed speech development and behavioral problems, were noted between the ages of 1 and 6 years. Other symptoms included sleeping and hearing problems, recurrent upper airway infections, diarrhea, and epilepsy. The clinical course varied remarkably and could be correlated with the molecular defects. The frequent pathogenic mutations p.R245H, p.Q380R, p.S66W, and c.1080delC were associated with the classical severe phenotype. Patients compound heterozygous for the p.S298P mutation in combination with 1 of the mutations associated with the classical severe phenotype had a significantly longer preservation of psychomotor functions and a longer survival. Two patients homozygous for the p.S298P mutation, and 4 patients from 3 families heterozygous for 3 missense variants not reported previously (p.T421R, p.P180L, and p.L12Q), showed a remarkably attenuated phenotype. INTERPRETATION: We report the natural history and mutational analysis in a large unbiased cohort of MPS IIIA patients. We demonstrate that the clinical spectrum of MPS IIIA is much broader than previously reported. A significant genotype-phenotype correlation was established in this cohort.
Subject(s)
Genetic Association Studies , Genotype , Phenotype , Adolescent , Adult , Behavioral Symptoms/etiology , Cells, Cultured , Child , Child, Preschool , Cohort Studies , DNA Mutational Analysis , Epilepsy/etiology , Female , Fibroblasts , Hearing Disorders/etiology , Humans , Hydrolases/genetics , Kaplan-Meier Estimate , Male , Middle Aged , Mucopolysaccharidosis III/complications , Mucopolysaccharidosis III/enzymology , Mucopolysaccharidosis III/genetics , Mucopolysaccharidosis III/pathology , Mutation/genetics , Pregnancy , Regression Analysis , Severity of Illness Index , Skin/pathology , Sleep Wake Disorders/etiology , Vision Disorders/etiology , Young AdultABSTRACT
We report on a patient with NF1 microdeletion and clinical manifestations that fulfill the diagnostic criteria for neurofibromatosis type 1 but also presenting features reminiscent of Proteus syndrome.
ABSTRACT
Mucopolysaccharidosis III D (Sanfilippo disease type D, MPS IIID) is a rare autosomal recessive lysosomal storage disorder previously described in only 20 patients. MPS IIID is caused by a deficiency of N-acetylglucosamine-6-sulphate sulphatase (GNS), one of the enzymes required for the degradation of heparan sulphate. So far only seven mutations in the GNS gene have been reported. The clinical phenotype of 12 new MPS IIID patients from 10 families was studied. Mutation analysis of GNS was performed in 16 patients (14 index cases). Clinical signs and symptoms of the MPS IIID patients appeared to be similar to previously described patients with MPS III. Early development was normal with onset of behavioral problems around the age of 4 years, followed by developmental stagnation, deterioration of verbal communication and subsequent deterioration of motor functions. Sequence analysis of the coding regions of the gene encoding GNS (GNS) resulted in the identification of 15 novel mutations: 3 missense mutations, 1 nonsense mutation, 4 splice site mutations, 3 frame shift mutations, 3 large deletions and 1 in-frame small deletion. They include the first missense mutations and a relatively high proportion of large rearrangements, which warrants the inclusion of quantitative techniques in routine mutation screening of the GNS gene.
Subject(s)
Mucopolysaccharidosis III/genetics , Sulfatases/deficiency , Sulfatases/genetics , Adolescent , Adult , Child , Child, Preschool , DNA Mutational Analysis , Female , Humans , Male , Mutation/genetics , Phenotype , Young AdultABSTRACT
The cause of hearing impairment has not been elucidated in a large proportion of patients. We screened by 1-Mb array-based comparative genomic hybridization (aCGH) 29 individuals with syndromic hearing impairment whose clinical features were not typical of known disorders. Rare chromosomal copy number changes were detected in eight patients, four de novo imbalances and four inherited from a normal parent. The de novo alterations define candidate chromosome segments likely to harbor dosage-sensitive genes related to hearing impairment, namely 1q23.3-q25.2, 2q22q23, 6p25.3 and 11q13.2-q13.4. The rare imbalances also present in normal parents might be casually associated with hearing impairment, but its role as a predisposition gene remains a possibility. Our results show that syndromic deafness is frequently associated with chromosome microimbalances (14-27%), and the use of aCGH for defining disease etiology is recommended.
Subject(s)
Chromosomal Instability/genetics , Hearing Loss/genetics , Child , Child, Preschool , Comparative Genomic Hybridization , Female , Gene Dosage , Humans , Male , SyndromeABSTRACT
Chromosome microdeletions or duplications are detected in 10-20% of patients with mental impairment and normal karyotypes. A few cases have been reported of mental impairment with microdeletions comprising tumor suppressor genes. By array-CGH we detected 4 mentally impaired individuals carrying de novo microdeletions sharing an overlapping segment of approximately 180 kb in 17p13.1. This segment encompasses 18 genes, including 3 involved in cancer, namely KCTD11/REN, DLG4/PSD95, and GPS2. Furthermore, in 2 of the patients, the deletions also included TP53, the most frequently inactivated gene in human cancers. The 3 tumor suppressor genes KCTD11, DLG4, and GPS2, in addition to the GABARAP gene, have a known or suspected function in neuronal development and are candidates for causing mental impairment in our patients. Among our 4 patients with deletions in 17p13.1, 3 were part of a Brazilian cohort of 300 mentally retarded individuals, suggesting that this segment may be particularly prone to rearrangements and appears to be an important cause (approximately 1%) of mental retardation. Further, the constitutive deletion of tumor suppressor genes in these patients, particularly TP53, probably confers a significantly increased lifetime risk for cancer and warrants careful oncological surveillance of these patients. Constitutional chromosome deletions containing tumor suppressor genes in patients with mental impairment or congenital abnormalities may represent an important mechanism linking abnormal phenotypes with increased risks of cancer.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 17/genetics , Genes, Tumor Suppressor , Intellectual Disability/genetics , Adaptor Proteins, Signal Transducing/genetics , Adolescent , Apoptosis Regulatory Proteins , Cell Cycle Proteins , Child , Child, Preschool , Chromosome Mapping , Comparative Genomic Hybridization , Disks Large Homolog 4 Protein , Female , Gene Dosage , Genes, p53 , Humans , In Situ Hybridization, Fluorescence , Intracellular Signaling Peptides and Proteins/genetics , Male , Membrane Proteins/genetics , Microtubule-Associated Proteins/genetics , Phenotype , Potassium Channels/genetics , TransferasesABSTRACT
Retrievals of atmospheric carbon dioxide (CO2) from space-borne measurements of backscattered near-infrared sunlight are hampered by aerosol and cirrus cloud scattering effects. We propose a retrieval approach that allows for the retrieval of a few effective aerosol parameters simultaneously with the CO2 total column by parameterizing particle amount, height distribution, and microphysical properties. Two implementations of the proposed method covering different spectral bands are tested for an ensemble of simulated nadir observations for aerosol (and cirrus) loaded scenes over low- and mid-latitudinal land surfaces. The residual aerosol-induced CO(2) errors are mostly below 1% up to aerosol optical thickness 0.5. The proposed methods also perform convincing for scenes where cirrus clouds of optical thickness 0.1 overlay the aerosol.