scholarly journals Lack of Overt Retinal Degeneration in a K42E Dhdds Knock-In Mouse Model of RP59

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 896 ◽  
Author(s):  
Sriganesh Ramachandra Rao ◽  
Steven J. Fliesler ◽  
Pravallika Kotla ◽  
Mai N. Nguyen ◽  
Steven J. Pittler
Keyword(s):  
Autosomal Recessive ◽  
Protein Glycosylation ◽  
Loss Of Function ◽  
Disease Mechanisms ◽  
Recessive Form ◽  
Pngase F ◽  
Gfap Immunoreactivity ◽  
Retinal Structure ◽  
And Control ◽  
Sd Oct

Dehydrodolichyl diphosphate synthase (DHDDS) is required for protein N-glycosylation in eukaryotic cells. A K42E point mutation in the DHDDS gene causes an autosomal recessive form of retinitis pigmentosa (RP59), which has been classified as a congenital disease of glycosylation (CDG). We generated K42E Dhdds knock-in mice as a potential model for RP59. Mice heterozygous for the Dhdds K42E mutation were generated using CRISPR/Cas9 technology and crossed to generate DhddsK42E/K42E homozygous mice. Spectral domain-optical coherence tomography (SD-OCT) was performed to assess retinal structure, relative to age-matched wild type (WT) controls. Immunohistochemistry against glial fibrillary acidic protein (GFAP) and opsin (1D4 epitope) was performed on retinal frozen sections to monitor gliosis and opsin localization, respectively, while lectin cytochemistry, plus and minus PNGase-F treatment, was performed to assess protein glycosylation status. Retinas of DhddsK42E/K42E mice exhibited grossly normal histological organization from 1 to 12 months of age. Anti-GFAP immunoreactivity was markedly increased in DhddsK42E/K42E mice, relative to controls. However, opsin immunolocalization, ConA labeling and PNGase-F sensitivity were comparable in mutant and control retinas. Hence, retinas of DhddsK42E/K42E mice exhibited no overt signs of degeneration, yet were markedly gliotic, but without evidence of compromised protein N-glycosylation. These results challenge the notion of RP59 as a DHDDS loss-of-function CDG and highlight the need to investigate unexplored RP59 disease mechanisms.

Changes of serum glycome in patients suffering from ovarian cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5047-5047
Author(s):  
Veronique Blanchard ◽  
Karina Biskup ◽  
Elena Ioana Braicu ◽  
Jalid Sehouli ◽  
Rudolf Tauber ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Serum Proteins ◽  
Early Stage ◽  
Research Work ◽  
Protein Glycosylation ◽  
Ca 125 ◽  
Pngase F ◽  
Cancer Tumor ◽  
Spss Software ◽  
And Control

5047 Background: Protein glycosylation plays an important role in many biological processes. Most human serum proteins, with the exception of albumin, are glycosylated. Glycosylation is known to be altered with development of diseases such as cancer. In the case of ovarian cancer, tumor markers among them CA-125 that are clinically used are known to have poor specificity. In addition, they fail to detect the disease at an early stage. Therefore, better biomarkers are needed. The aim of the present research work is to identify new potential glycan biomarkers by analyzing the serum N-glycome of patients suffering from ovarian cancer Methods: Serum was collected from 67 patients as well as from 33 healthy age-matching women. N-glycans were released from 10 ul serum by PNGase F digestion, permethylated and subsequently analyzed by means of MALDI-TOF mass spectrometry. The SPSS software was used for the statistical analysis. Results: The N-glycome of patients was found to have more fucosylated structures, especially in tri- and tetraantennary sialylated glycans. The PCA analysis indicates that there are significant differences between the glycome of ovarian cancer patients in all stages of the disease and the glycome of healthy controls. We identified 14 potential structures that were divided in two categories, one of monofucosylated structures with high antennarity (sensitivity 94%, specificity 97%) and one containing high-mannose structures and an asialylated structures (sensitivity 97%, specificity 97%). Conclusions: Our study is the first trial to identify major differences between ovarian cancer sera and control sera, which could potentially be used in the future as biomarkers.

scholarly journals Abnormal proplatelet formation and emperipolesis in cultured human megakaryocytes from gray platelet syndrome patients

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Christian A. Di Buduo ◽  
Maria Adele Alberelli ◽  
Ana C. Glembotsky ◽  
Gianmarco Podda ◽  
Paola R. Lev ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Hematopoietic Progenitor Cells ◽  
Loss Of Function ◽  
Hematopoietic Progenitor ◽  
Autosomal Recessive Form ◽  
Recessive Form ◽  
Gray Platelet Syndrome ◽  
Marrow Fibrosis ◽  
Platelet Formation

Abstract The Gray Platelet Syndrome (GPS) is a rare inherited bleeding disorder characterized by deficiency of platelet α-granules, macrothrombocytopenia and marrow fibrosis. The autosomal recessive form of GPS is linked to loss of function mutations in NBEAL2, which is predicted to regulate granule trafficking in megakaryocytes, the platelet progenitors. We report the first analysis of cultured megakaryocytes from GPS patients with NBEAL2 mutations. Megakaryocytes cultured from peripheral blood or bone marrow hematopoietic progenitor cells from four patients were used to investigate megakaryopoiesis, megakaryocyte morphology and platelet formation. In vitro differentiation of megakaryocytes was normal, whereas we observed deficiency of megakaryocyte α-granule proteins and emperipolesis. Importantly, we first demonstrated that platelet formation by GPS megakaryocytes was severely affected, a defect which might be the major cause of thrombocytopenia in patients. These results demonstrate that cultured megakaryocytes from GPS patients provide a valuable model to understand the pathogenesis of GPS in humans.

Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia

2020 ◽  
Author(s):  
Yousef Binamer ◽  
Muzamil A. Chisti
Keyword(s):  
Autosomal Recessive ◽  
Common Mechanism ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Skin Atrophy ◽  
Whole Exome ◽  
Infancy And Childhood ◽  
Genetics And Genomics ◽  
New Feature ◽  
Generation Sequencing

AbstractKindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene GALNT14

2019 ◽  
Vol 19 (9) ◽  
pp. 683-687 ◽  
Author(s):  
Tawfiq Froukh ◽  
Ammar Hawwari
Keyword(s):  
Strong Evidence ◽  
Autosomal Recessive ◽  
Eye Diseases ◽  
Initial Reaction ◽  
Genetic Contribution ◽  
Loss Of Function ◽  
Consanguineous Family ◽  
Truncated Protein ◽  
Threonine Residue ◽  
Whole Exome

Background: Keratoconus (KC) is usually bilateral, noninflammatory progressive corneal ectasia in which the cornea becomes progressively thin and conical. Despite the strong evidence of genetic contribution in KC, the etiology of KC is not understood in most cases. Methods: In this study, we used whole-exome sequencing to identify the genetic cause of KC in two sibs in a consanguineous family. The Homozygous frameshift variant NM_001253826.1:c.60delC;p.Leu21Cysfs*6 was identified in the gene Nacetylgalactosaminyltransferase 14 (GALNT14). The variant does not exist in all public databases neither in our internal exome database. Moreover, no database harbours homozygous loss of function variants in the candidate gene. Result: GALNT14 catalyses the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D- galactosamine residue to a serine or threonine residue on target proteins especially Mucins. Conclusion: As alterations of mucin’s glycosylation are linked to a number of eye diseases, we demonstrate in this study an association between the truncated protein GALNT14 and KC.

scholarly journals Identification of a novel homozygous loss-of-function mutation in FUCA1 gene causing severe fucosidosis: A case report

2021 ◽  
Vol 49 (4) ◽  
pp. 030006052110059
Author(s):  
Xinwen Zhang ◽  
Shaozhi Zhao ◽  
Hongwei Liu ◽  
Xiaoyan Wang ◽  
Xiaolei Wang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Lysosomal Storage Disorder ◽  
Autosomal Recessive ◽  
Signs And Symptoms ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Wild Type ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Exon 1

Fucosidosis is a rare lysosomal storage disorder characterized by deficiency of α-L-fucosidase with an autosomal recessive mode of inheritance. Here, we describe a 4-year-old Chinese boy with signs and symptoms of fucosidosis but his parents were phenotypically normal. Whole exome sequencing (WES) identified a novel homozygous single nucleotide deletion (c.82delG) in the exon 1 of the FUCA1 gene. This mutation will lead to a frameshift which will result in the formation of a truncated FUCA1 protein (p.Val28Cysfs*105) of 132 amino acids approximately one-third the size of the wild type FUCA1 protein (466 amino acids). Both parents were carrying the mutation in a heterozygous state. This study expands the mutational spectrum of the FUCA1 gene associated with fucosidosis and emphasises the benefits of WES for accurate and timely clinical diagnosis of this rare disease.

scholarly journals ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants

Neurogenetics ◽  
2021 ◽  
Author(s):  
Katja Kloth ◽  
Bernarda Lozic ◽  
Julia Tagoe ◽  
Mariëtte J. V. Hoffer ◽  
Amelie Van der Ven ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Neuronal Development ◽  
Autosomal Dominant ◽  
Tissue Expression ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Ankyrin G ◽  
Phenotypic Spectrum ◽  
And Function ◽  
Neurodevelopmental Phenotype

AbstractANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum.

scholarly journals Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Samina Yasin ◽  
Outi Makitie ◽  
Sadaf Naz
Keyword(s):  
Short Stature ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Loss Of Function ◽  
Case Presentation ◽  
Pathogenic Variants ◽  
Skeletal Malformations ◽  
Tarsal Bones ◽  
The Family ◽  
Heterozygous Carriers

Abstract Background Loss of function or gain of function variants of Filamin B (FLNB) cause recessive or dominant skeletal disorders respectively. Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive disorder characterized by short stature, fused vertebrae and fusion of carpal and tarsal bones. We present a novel FLNB homozygous pathogenic variant and present a carrier of the variant with short height. Case presentation We describe a family with five patients affected with skeletal malformations, short stature and vertebral deformities. Exome sequencing revealed a novel homozygous frameshift variant c.2911dupG p.(Ala971GlyfsTer122) in FLNB, segregating with the phenotype in the family. The variant was absent in public databases and 100 ethnically matched control chromosomes. One of the heterozygous carriers of the variant had short stature. Conclusion Our report expands the genetic spectrum of FLNB pathogenic variants. It also indicates a need to assess the heights of other carriers of FLNB recessive variants to explore a possible role in idiopathic short stature.

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