scholarly journals Miglustat Therapy for SCARB2-Associated Action Myoclonus–Renal Failure Syndrome

2021 ◽  
Vol 7 (5) ◽  
pp. e614
Author(s):  
Imran H. Quraishi ◽  
Anna M. Szekely ◽  
Anushree C. Shirali ◽  
Pramod K. Mistry ◽  
Lawrence J. Hirsch
Keyword(s):  
Renal Failure ◽  
Scavenger Receptor ◽  
Gene Mutations ◽  
Substrate Reduction Therapy ◽  
Neurologic Symptoms ◽  
Substrate Reduction ◽  
Course Of Action ◽  
Whole Exome ◽  
Action Myoclonus ◽  
Class B

ObjectiveWe evaluated whether substrate reduction therapy with miglustat could alter the course of action myoclonus–renal failure syndrome (AMRF), a rare, progressive myoclonic epilepsy with early mortality caused by scavenger receptor class B member 2 (SCARB2) gene mutations.MethodsWe identified an AMRF patient with a biallelic combination of SCARB2 mutations determined by whole exome sequencing. SCARB2 encodes a protein that traffics β-glucocerebrosidase to the lysosomal membrane. Mutations lead to a complex pattern of glucosylceramide accumulation and neurologic symptoms including progressive action myoclonus, seizures, and ataxia. We then evaluated the effect of inhibiting glucosylceramide synthesis, as is used in Gaucher disease. The patient was treated for 3 years with miglustat after several years of steady worsening.ResultsProgression of myoclonus halted, dysphagia resolved, some skills were reacquired, and seizures remained well controlled.ConclusionsThe response suggests that neurologic symptoms of SCARB2-associated AMRF could be ameliorated, at least partly, by targeting glycosphingolipid metabolism with available medications.

scholarly journals HDL modification by secretory phospholipase A2 promotes scavenger receptor class B type I interaction and accelerates HDL catabolism

2000 ◽  
Vol 41 (11) ◽  
pp. 1849-1857 ◽  
Author(s):  
Frederick C. de Beer ◽  
Patrice M. Connell ◽  
J. Yu ◽  
Maria C. de Beer ◽  
Nancy R. Webb ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Scavenger Receptor ◽  
Type I ◽  
Secretory Phospholipase A2 ◽  
Secretory Phospholipase ◽  
Scavenger Receptor Class ◽  
Class B

scholarly journals The identification of novel gene mutations for degenerative lumbar spinal stenosis using whole-exome sequencing in a Chinese cohort

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xin Jiang ◽  
Dong Chen
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Spinal Stenosis ◽  
Lumbar Spinal Stenosis ◽  
Gene Mutations ◽  
Specific Gene ◽  
Single Nucleotide ◽  
Degenerative Lumbar Spinal Stenosis ◽  
Whole Exome ◽  
Lumbar Spinal

Abstract Background Degenerative lumbar spinal stenosis (DLSS) is a common lumbar disease that requires surgery. Previous studies have indicated that genetic mutations are implicated in DLSS. However, studies on specific gene mutations are scarce. Whole-exome sequencing (WES) is a valuable research tool that identifies disease-causing genes and could become an effective strategy to investigate DLSS pathogenesis. Methods From January 2016 to December 2017, we recruited 50 unrelated patients with symptoms consistent with DLSS and 25 unrelated healthy controls. We conducted WES and exome data analysis to identify susceptible genes. Allele mutations firstly identified potential DLSS variants in controls to the patients’ group. We conducted a site-based association analysis to identify pathogenic variants using PolyPhen2, SIFT, Mutation Taster, Combined Annotation Dependent Depletion, and Phenolyzer algorithms. Potential variants were further confirmed using manual curation and validated using Sanger sequencing. Results In this cohort, the major classification variant was missense_mutation, the major variant type was single nucleotide polymorphism (SNP), and the major single nucleotide variation was C > T. Multiple SNPs in 34 genes were identified when filtered allele mutations in controls to retain only patient mutations. Pathway enrichment analyses revealed that mutated genes were mainly enriched for immune response-related signaling pathways. Using the Novegene database, site-based associations revealed several novel variants, including HLA-DRB1, PARK2, ACTR8, AOAH, BCORL1, MKRN2, NRG4, NUP205 genes, etc., were DLSS related. Conclusions Our study revealed that deleterious mutations in several genes might contribute to DLSS etiology. By screening and confirming susceptibility genes using WES, we provided more information on disease pathogenesis. Further WES studies incorporating larger DLSS patient cohorts are required to comprehend the genetic landscape of DLSS pathophysiology fully.

scholarly journals Whole-exome mutational landscape of neuroendocrine carcinomas of the gallbladder

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Fatao Liu ◽  
Yongsheng Li ◽  
Dongjian Ying ◽  
Shimei Qiu ◽  
Yong He ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Large Cell ◽  
Molecular Signatures ◽  
Single Nucleotide Variants ◽  
Oncogenic Signaling ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Deadly Disease ◽  
Oncogenic Signaling Pathways ◽  
Neuroendocrine Carcinomas

AbstractNeuroendocrine carcinoma (NEC) of the gallbladder (GB-NEC) is a rare but extremely malignant subtype of gallbladder cancer (GBC). The genetic and molecular signatures of GB-NEC are poorly understood; thus, molecular targeting is currently unavailable. In the present study, we applied whole-exome sequencing (WES) technology to detect gene mutations and predicted somatic single-nucleotide variants (SNVs) in 15 cases of GB-NEC and 22 cases of general GBC. In 15 GB-NECs, the C > T mutation was predominant among the 6 types of SNVs. TP53 showed the highest mutation frequency (73%, 11/15). Compared with neuroendocrine carcinomas of other organs, significantly mutated genes (SMGs) in GB-NECs were more similar to those in pulmonary large-cell neuroendocrine carcinomas (LCNECs), with driver roles for TP53 and RB1. In the COSMIC database of cancer-related genes, 211 genes were mutated. Strikingly, RB1 (4/15, 27%) and NAB2 (3/15, 20%) mutations were found specifically in GB-NECs; in contrast, mutations in 29 genes, including ERBB2 and ERBB3, were identified exclusively in GBC. Mutations in RB1 and NAB2 were significantly related to downregulation of the RB1 and NAB2 proteins, respectively, according to immunohistochemical (IHC) data (p values = 0.0453 and 0.0303). Clinically actionable genes indicated 23 mutated genes, including ALK, BRCA1, and BRCA2. In addition, potential somatic SNVs predicted by ISOWN and SomVarIUS constituted 6 primary COSMIC mutation signatures (1, 3, 30, 6, 7, and 13) in GB-NEC. Genes carrying somatic SNVs were enriched mainly in oncogenic signaling pathways involving the Notch, WNT, Hippo, and RTK-RAS pathways. In summary, we have systematically identified the mutation landscape of GB-NEC, and these findings may provide mechanistic insights into the specific pathogenesis of this deadly disease.

scholarly journals A hSCARB2-transgenic mouse model for Coxsackievirus A16 pathogenesis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yanli Chen ◽  
Heng Li ◽  
Jinxi Yang ◽  
Huiwen Zheng ◽  
Lei Guo ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Scavenger Receptor ◽  
Clinical Signs ◽  
Foot And Mouth Disease ◽  
Infection Process ◽  
Coxsackievirus A16 ◽  
Class B ◽  
Suitable Animal Model ◽  
Limited Host Range ◽  
Brain Tissues

Abstract Background Coxsackievirus A16 (CA16) is one of the neurotropic pathogen that has been associated with severe neurological forms of hand, foot, and mouth disease (HFMD), but its pathogenesis is not yet clear. The limited host range of CA16 make the establishment of a suitable animal model that can recapitulate the neurological pathology observed in human HFMD more difficult. Because the human scavenger receptor class B, member 2 (hSCARB2) is a cellular receptor for CA16, we used transgenic mice bearing human SCARB2 and nasally infected them with CA16 to study the pathogenicity of the virus. Methods Coxsackievirus A16 was administered by intranasal instillation to groups of hSCARB2 transgenic mice and clinical signs were observed. Sampled at different time-points to document and characterize the mode of viral dissemination, pathological change and immune response of CA16 infection. Results Weight loss and virus replication in lung and brain were observed in hSCARB2 mice infected with CA16, indicating that these animals could model the neural infection process. Viral antigens were observed in the alveolar epithelia and brainstem cells. The typical histopathology was interstitial pneumonia with infiltration of significant lymphocytes into the alveolar interstitial in lung and diffuse punctate hemorrhages in the capillaries of the brainstem. In addition, we detected the expression levels of inflammatory cytokines and detected high levels of interleukin IL-1β, IL-6, IL-18, and IFN-γ in nasal mucosa, lungs and brain tissues. Conclusions The hSCARB2-transgenic mice can be productively infected with CA16 via respiratory route and exhibited a clear tropism to lung and brain tissues, which can serve as a model to investigate the pathogenesis of CA16 associated respiratory and neurological disease.

scholarly journals A Case Report of a Prenatally Missed Mowat-Wilson Syndrome With Isolated Corpus Callosum Agenesis

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110065
Author(s):  
Nesrin Şenbil ◽  
Zeynep Arslan ◽  
Derya Beyza Sayın Kocakap ◽  
Yasemin Bilgili
Keyword(s):  
Corpus Callosum ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Gene Mutations ◽  
Hirschsprung Disease ◽  
Agenesis Of Corpus Callosum ◽  
Whole Exome ◽  
Congenital Cardiac Anomalies ◽  
History Of ◽  
Gene Mutation Analysis

Mowat–Wilson syndrome (MWS) is an autosomal dominant genetic disorder caused by ZEB2 gene mutations, manifesting with unique facial characteristics, moderate to severe intellectual problems, and congenital malformations as Hirschsprung disease, genital and ophthalmological anomalies, and congenital cardiac anomalies. Herein, a case of 1-year-old boy with isolated agenesis of corpus callosum (IACC) in the prenatal period is presented. He was admitted postnatally with Hirschsprung disease (HSCR), hypertelorism, uplifted earlobes, deeply set eyes, frontal bossing, oval-shaped nasal tip, ‘‘M’’ shaped upper lip, opened mouth and prominent chin, and developmental delay. Hence, MWS was primarily considered and confirmed by the ZEB2 gene mutation analysis. His karyotype was normal. He had a history of having a prenatally terminated brother with similar features. Antenatally detected IACC should prompt a detailed investigation including karyotype and microarray; even if they are normal then whole exome sequencing (WES) should be done.

MS81 LIVER-SPECIFIC LIPOPLEXES FOR THE KNOCKDOWN OF SCAVENGER RECEPTOR CLASS B TYPE I

2010 ◽  
Vol 11 (2) ◽  
pp. 126
Author(s):  
K. Duwensee ◽  
I. Tancevski ◽  
E. Demetz ◽  
P. Eller ◽  
C. Heim ◽  
...  
Keyword(s):  
Scavenger Receptor ◽  
Type I ◽  
Scavenger Receptor Class ◽  
Class B
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