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  • 1
    Language: English
    In: Human mutation, 2017-10, Vol.38 (10), p.1394-1401
    Description: Glycosylphosphatidylinositol (GPI) is a glycolipid that tethers more than 150 different proteins to the cell surface. Aberrations in biosynthesis of GPI anchors cause congenital disorders of glycosylation with clinical features including intellectual disability (ID), seizures, and facial dysmorphism. Here, we present two siblings with ID, cerebellar hypoplasia, cerebellar ataxia, early‐onset seizures, and minor facial dysmorphology. Using exome sequencing, we identified a homozygous nonsense variant (NM_001127178.1:c.1640G〉A, p.Trp547*) in the gene Phosphatidylinositol Glycan Anchor Biosynthesis, Class G (PIGG) in both the patients. Variants in several other GPI anchor synthesis genes lead to a reduced expression of GPI‐anchored proteins (GPI‐APs) that can be measured by flow cytometry. No significant differences in GPI‐APs could be detected in patient granulocytes, consistent with recent findings. However, fibroblasts showed a reduced global level of GPI anchors and of specific GPI‐linked markers. These findings suggest that fibroblasts might be more sensitive to pathogenic variants in GPI synthesis pathway and are well suited to screen for GPI‐anchor deficiencies. Based on genetic and functional evidence, we confirm that pathogenic variants in PIGG cause an ID syndrome, and we find that loss of function of PIGG is associated with GPI deficiency. Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors proteins to the cell surface. Pathogenic variation in genes involved in GPI synthesis is associated with intellectual disability syndromes caused by GPI deficiency. Our results show that nonsense variation in the PIGG gene is associated with intellectual disability, but that expression of GPI‐anchored proteins (GPI‐AP) in patients differs between cell types, with reduced expression in patient fibroblasts, but not in patient granulocytes.
    Subject(s): Age ; Biosynthesis ; Cell surface ; Cerebellar ataxia ; Cerebellar Ataxia - genetics ; Cerebellar Ataxia - physiopathology ; Cerebellum ; Cerebellum - abnormalities ; Cerebellum - physiopathology ; Child ; Child, Preschool ; Developmental Disabilities - genetics ; Developmental Disabilities - physiopathology ; Exome sequencing ; Female ; Fibroblasts ; Flow Cytometry ; Gene Expression ; Genetic disorders ; Glycosylation ; Glycosylphosphatidylinositol ; Glycosylphosphatidylinositols - chemistry ; Glycosylphosphatidylinositols - deficiency ; Glycosylphosphatidylinositols - genetics ; GPI deficiency ; Humans ; Hypoplasia ; Intellectual disability ; Intellectual Disability - genetics ; Intellectual Disability - physiopathology ; Leukocytes (granulocytic) ; Lipids ; Male ; Medical and Health Sciences ; Medical research ; Medicin och hälsovetenskap ; Medicine, Experimental ; Membrane Proteins - genetics ; Nervous System Malformations - genetics ; Nervous System Malformations - physiopathology ; Pedigree ; Phosphatidylinositol ; Phosphotransferases (Alcohol Group Acceptor) - chemistry ; Phosphotransferases (Alcohol Group Acceptor) - genetics ; Physiological aspects ; PIGG ; Proteins ; Seizures ; Seizures (Medicine) ; Seizures - genetics ; Seizures - physiopathology ; Siblings ; Whole Exome Sequencing
    ISSN: 1059-7794
    ISSN: 1098-1004
    E-ISSN: 1098-1004
    Source: Hellenic Academic Libraries Link
    Source: SWEPUB Freely available online
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  • 2
    Language: English
    In: Nucleic acids research, 2020-07-02, Vol.48 (W1), p.W162-W169
    Description: Abstract VarFish is a user-friendly web application for the quality control, filtering, prioritization, analysis, and user-based annotation of DNA variant data with a focus on rare disease genetics. It is capable of processing variant call files with single or multiple samples. The variants are automatically annotated with population frequencies, molecular impact, and presence in databases such as ClinVar. Further, it provides support for pathogenicity scores including CADD, MutationTaster, and phenotypic similarity scores. Users can filter variants based on these annotations and presumed inheritance pattern and sort the results by these scores. Variants passing the filter are listed with their annotations and many useful link-outs to genome browsers, other gene/variant data portals, and external tools for variant assessment. VarFish allows users to create their own annotations including support for variant assessment following ACMG-AMP guidelines. In close collaboration with medical practitioners, VarFish was designed for variant analysis and prioritization in diagnostic and research settings as described in the software's extensive manual. The user interface has been optimized for supporting these protocols. Users can install VarFish on their own in-house servers where it provides additional lab notebook features for collaborative analysis and allows re-analysis of cases, e.g. after update of genotype or phenotype databases.
    Subject(s): AcademicSubjects ; SCI00010 ; Web Server Issue
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 3
    Language: English
    In: Nature communications, 2021-12-16, Vol.12 (1), p.7322-7322
    Description: Blastocyst-derived stem cell lines were shown to self-organize into embryo-like structures in 3D cell culture environments. Here, we provide evidence that embryo-like structures can be generated solely based on transcription factor-mediated reprogramming of embryonic stem cells in a simple 3D co-culture system. Embryonic stem cells in these cultures self-organize into elongated, compartmentalized embryo-like structures reflecting aspects of the inner regions of the early post-implantation embryo. Single-cell RNA-sequencing reveals transcriptional profiles resembling epiblast, primitive-/visceral endoderm, and extraembryonic ectoderm of early murine embryos around E4.5-E5.5. In this stem cell-based embryo model, progression from rosette formation to lumenogenesis accompanied by progression from naïve- to primed pluripotency was observed within Epi-like cells. Additionally, lineage specification of primordial germ cells and distal/anterior visceral endoderm-like cells was observed in epiblast- or visceral endoderm-like compartments, respectively. The system presented in this study allows for fast and reproducible generation of embryo-like structures, providing an additional tool to study aspects of early embryogenesis.
    Subject(s): Animals ; Blastocyst - cytology ; Blastocyst - metabolism ; Cell culture ; Cell Culture Techniques, Three Dimensional ; Cell lines ; Cellular Reprogramming ; Ectoderm ; Elongated structure ; Embryo cells ; Embryo, Mammalian - embryology ; Embryo, Mammalian - metabolism ; Embryogenesis ; Embryoid Bodies - cytology ; Embryoid Bodies - metabolism ; Embryonic Development ; Embryonic growth stage ; Embryonic Stem Cells - cytology ; Embryonic Stem Cells - metabolism ; Embryos ; Endoderm ; Endoderm - embryology ; Endoderm - metabolism ; Gene Expression Regulation, Developmental ; Gene sequencing ; Germ cells ; Implantation ; Mice ; Pluripotency ; RNA-Seq ; Rosette formation ; Stem cell transplantation ; Stem cells
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 4
    Language: English
    In: Scientific reports, 2018, Vol.8 (1), p.14611-5
    Description: A genome-wide evaluation of the effects of ionizing radiation on mutation induction in the mouse germline has identified multisite de novo mutations (MSDNs) as marker for previous exposure. Here we present the results of a small pilot study of whole genome sequencing in offspring of soldiers who served in radar units on weapon systems that were emitting high-frequency radiation. We found cases of exceptionally high MSDN rates as well as an increased mean in our cohort: While a MSDN mutation is detected in average in 1 out of 5 offspring of unexposed controls, we observed 12 MSDNs in altogether 18 offspring, including a family with 6 MSDNs in 3 offspring. Moreover, we found two translocations, also resulting from neighboring mutations. Our findings indicate that MSDNs might be suited in principle for the assessment of DNA damage from ionizing radiation also in humans. However, as exact person-related dose values in risk groups are usually not available, the interpretation of MSDNs in single families would benefit from larger molecular epidemiologic studies on this new biomarker.
    Subject(s): DNA damage ; Genomes ; Ionizing radiation ; Mutation ; Progeny ; Risk groups ; Translocation
    ISSN: 2045-2322
    E-ISSN: 2045-2322
    Source: Nature Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
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  • 5
    Language: English
    In: Journal of bone and mineral research, 2020-07, Vol.35 (7), p.1322-1332
    Description: ABSTRACT Osteosclerotic metaphyseal dysplasia (OSMD) is a rare autosomal recessive sclerosing skeletal dysplasia. We report on a 34‐year‐old patient with sandwich vertebrae, platyspondyly, osteosclerosis of the tubular bones, pathologic fractures, and anemia. In the third decade, he developed osteonecrosis of the jaws, which was progressive in spite of repeated surgical treatment over a period of 11 years. An iliac crest bone biopsy revealed the presence of hypermineralized cartilage remnants, large multinucleated osteoclasts with abnormal morphology, and inadequate bone resorption typical for osteoclast‐rich osteopetrosis. After exclusion of mutations in TCIRG1 and CLCN7 we performed trio‐based exome sequencing. The novel homozygous splice‐site mutation c.261G〉A in the gene LRRK1 was found and co‐segregated with the phenotype in the family. cDNA sequencing showed nearly complete skipping of exon 3 leading to a frameshift (p.Ala34Profs*33). Osteoclasts differentiated from the patient's peripheral blood monocytes were extremely large. Instead of resorption pits these cells were only capable of superficial erosion. Phosphorylation of L‐plastin at position Ser5 was strongly reduced in patient‐derived osteoclasts showing a loss of function of the mutated LRRK1 kinase protein. Our analysis indicates a strong overlap of LRRK1‐related OSMD with other forms of intermediate osteopetrosis, but an exceptional abnormality of osteoclast resorption. Like in other osteoclast pathologies an increased risk for progressive osteonecrosis of the jaws should be considered in OSMD, an intermediate form of osteopetrosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
    Subject(s): Biopsy ; Bone dysplasia ; Bone resorption ; Cartilage ; Fractures ; Iliac crest ; LRRK1 ; Monocytes ; Mutation ; NEXT GENERATION SEQUENCING ; Osteoclasts ; Osteonecrosis ; OSTEOPETROSIS ; Osteosclerosis ; OSTEOSCLEROTIC METAPHYSEAL DYSPLASIA ; Peripheral blood ; Phenotypes ; Phosphorylation ; Skeleton ; Spine ; TRIO‐BASED EXOME SEQUENCING ; Vertebrae
    ISSN: 0884-0431
    E-ISSN: 1523-4681
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 6
    Language: English
    In: American journal of human genetics, 2019-08-01, Vol.105 (2), p.395-402
    Description: The glycosylphosphatidylinositol (GPI) anchor links over 150 proteins to the cell surface and is present on every cell type. Many of these proteins play crucial roles in neuronal development and function. Mutations in 18 of the 29 genes implicated in the biosynthesis of the GPI anchor have been identified as the cause of GPI biosynthesis deficiencies (GPIBDs) in humans. GPIBDs are associated with intellectual disability and seizures as their cardinal features. An essential component of the GPI transamidase complex is PIGU, along with PIGK, PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GPI anchor in the endoplasmic reticulum (ER). Here, we report two homozygous missense mutations (c.209T〉A [p.Ile70Lys] and c.1149C〉A [p.Asn383Lys]) in five individuals from three unrelated families. All individuals presented with global developmental delay, severe-to-profound intellectual disability, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Using multicolor flow cytometry, we determined a characteristic profile for GPI transamidase deficiency. On granulocytes this profile consisted of reduced cell-surface expression of fluorescein-labeled proaerolysin (FLAER), CD16, and CD24, but not of CD55 and CD59; additionally, B cells showed an increased expression of free GPI anchors determined by T5 antibody. Moreover, computer-assisted facial analysis of different GPIBDs revealed a characteristic facial gestalt shared among individuals with mutations in PIGU and GPAA1. Our findings improve our understanding of the role of the GPI transamidase complex in the development of nervous and skeletal systems and expand the clinical spectrum of disorders belonging to the group of inherited GPI-anchor deficiencies.
    Subject(s): Acyltransferases - genetics ; Adolescent ; Adult ; Amino Acid Sequence ; automated facial analysis ; Brain Diseases - etiology ; Brain Diseases - pathology ; Child ; Child, Preschool ; deep phenotyping ; epilepsy ; Epilepsy - etiology ; Epilepsy - pathology ; Female ; Gene mutations ; Genetic aspects ; Genetics & Heredity ; glycosylphosphatidylinositol ; Glycosylphosphatidylinositols ; Glycosylphosphatidylinositols - biosynthesis ; Glycosylphosphatidylinositols - deficiency ; Glycosylphosphatidylinositols - genetics ; GPIBD ; Humans ; Infant ; Infant, Newborn ; inherited GPI deficiency ; Intellectual Disability - etiology ; Intellectual Disability - pathology ; Life Sciences & Biomedicine ; Male ; Mental retardation ; multicolor flow cytometry ; Mutation ; Pedigree ; Physiological aspects ; PIGU ; Report ; Research ; Risk factors ; Science & Technology ; Seizures - genetics ; Seizures - pathology ; Sequence Homology ; Young Adult
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: PubMed Central
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  • 7
    Language: English
    In: The Journal of clinical investigation, 2019-12-02, Vol.129 (12), p.5123-5136
    Description: Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored (GPI-anchored) proteins, resulting from a mutation in the X-linked gene PIGA. Here we report on a set of patients in whom PNH results instead from biallelic mutation of PIGT on chromosome 20. These PIGT-PNH patients have clinically typical PNH, but they have in addition prominent autoinflammatory features, including recurrent attacks of aseptic meningitis. In all these patients we find a germ-line point mutation in one PIGT allele, whereas the other PIGT allele is removed by somatic deletion of a 20q region comprising maternally imprinted genes implicated in myeloproliferative syndromes. Unlike in PIGA-PNH cells, GPI is synthesized in PIGT-PNH cells and, since its attachment to proteins is blocked, free GPI is expressed on the cell surface. From studies of patients' leukocytes and of PIGT-KO THP-1 cells we show that, through increased IL-1 beta secretion, activation of the lectin pathway of complement and generation of C5b-9 complexes, free GPI is the agent of autoinflammation. Eculizumab treatment abrogates not only intravascular hemolysis, but also autoinflammation. Thus, PIGT-PNH differs from PIGA-PNH both in the mechanism of clonal expansion and in clinical manifestations.
    Subject(s): Abridged Index Medicus ; B cells ; Complement ; Gene mutations ; Genetic aspects ; Glycobiology ; Hematology ; Inflammation ; Lectins ; Life Sciences & Biomedicine ; Medical research ; Medicine, Experimental ; Medicine, Research & Experimental ; Research & Experimental Medicine ; Science & Technology
    ISSN: 0021-9738
    E-ISSN: 1558-8238
    Source: Freely Accessible Science Journals
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: PubMed Central
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  • 8
    Language: English
    In: BMC medical genomics, 2019-01-10, Vol.12 (1), p.6-6
    Description: BackgroundTwo interstitial microdeletions Xp11.22 including the CLCN5 and SHROOM4 genes were recently reported in a male individual affected with Dent disease, short stature, psychomotor delay and minor facial anomalies. Dent disease, characterized by a specific renal phenotype, is caused by truncating mutations of CLCN5 in the majority of affected cases.Case presentationHere, we present clinical and molecular findings in a male patient with clinical signs of Dent disease, developmental delay, short stature, microcephaly, and facial dysmorphism. Using molecular karyotyping we identified a hemizygous interstitial microdeletion Xp11.23p.11.22 of about 700kb, which was inherited from his asymptomatic mother. Among the six deleted genes is CLCN5, which explains the renal phenotype in our patient. SHROOM4, which is partially deleted in this patient, is involved in neuronal development and was shown to be associated with X-linked intellectual disability. This is a candidate gene, the loss of which is thought to be associated with his further clinical manifestations.To rule out mutations in other genes related to intellectual disability, whole exome sequencing was performed. No other pathogenic variants that could explain the phenotypic features, were found.ConclusionWe compared the clinical findings of the patient presented here with the reported case with an Xp11.22 microdeletion including CLCN5 and SHROOM4 and re-defined the phenotypic spectrum associated with this microdeletion.
    Subject(s): Age ; Bioinformatics ; Case Report ; Child, Preschool ; Chloride Channels - genetics ; Chromosome Deletion ; CLCN5 ; Cytoskeletal Proteins - genetics ; Dent disease ; Dent Disease - complications ; Dent Disease - genetics ; Dent's disease ; Disease ; Dwarfism - complications ; Female ; Genes ; Genetic aspects ; Genetics ; Genetics & Heredity ; Genomes ; Genotype & phenotype ; Humans ; Intellectual disabilities ; Intellectual Disability - complications ; Karyotyping ; Life Sciences & Biomedicine ; Male ; Mental retardation ; Microcephaly ; Microcephaly - complications ; Microencephaly ; Mutation ; Patients ; Pedigree ; Phenotypes ; Proteins ; Science & Technology ; SHROOM4 ; Stature, Short ; Usage
    ISSN: 1755-8794
    E-ISSN: 1755-8794
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 9
    Language: English
    In: Human mutation, 2016-08, Vol.37 (8), p.737-744
    Description: ABSTRACT HPMRS or Mabry syndrome is a heterogeneous glycosylphosphatidylinositol (GPI) anchor deficiency that is caused by an impairment of synthesis or maturation of the GPI‐anchor. The expressivity of the clinical features in HPMRS varies from severe syndromic forms with multiple organ malformations to mild nonsyndromic intellectual disability. In about half of the patients with the clinical diagnosis of HPMRS, pathogenic mutations can be identified in the coding region in one of the six genes, one among them is PGAP3. In this work, we describe a screening approach with sequence specific baits for transcripts of genes of the GPI pathway that allows the detection of functionally relevant mutations also including introns and the 5′ and 3′ UTR. By this means, we also identified pathogenic noncoding mutations, which increases the diagnostic yield for HPMRS on the basis of intellectual disability and elevated serum alkaline phosphatase. In eight affected individuals from different ethnicities, we found seven novel pathogenic mutations in PGAP3. Besides five missense mutations, we identified an intronic mutation, c.558‐10G〉A, that causes an aberrant splice product and a mutation in the 3′UTR, c.*559C〉T, that is associated with substantially lower mRNA levels. We show that our novel screening approach is a useful rapid detection tool for alterations in genes coding for key components of the GPI pathway. We describe 8 subjects with Mabry syndrome who have mutations in PGAP3. The non‐coding pathogenic mutations could be identified by targeted enrichment of all gene transcripts of the GPI‐anchor synthesis pathway. The differential analysis of c‐ and gDNA revealed an almost monoallelic expression and pointed to a 3’UTR mutation with a regulatory effect. This finding suggests that PGAP3 is dosage sensitive and a five‐ to ten fold decrease of a functional transcript results in a GPI‐anchor deficiency.
    Subject(s): 3' Untranslated Regions ; Abnormalities, Multiple - genetics ; Abnormalities, Multiple - pathology ; Adolescent ; Adult ; Cells, Cultured ; Child ; Child, Preschool ; Female ; Genes ; Genetic aspects ; Genetic Predisposition to Disease ; Genetic transcription ; Humans ; hyperphosphatasia with mental retardation ; Intellectual disabilities ; intellectual disability ; Intellectual Disability - genetics ; Intellectual Disability - pathology ; Introns ; Mabry syndrome ; Male ; Mental illness ; Mental retardation ; Mutation ; Mutation, Missense ; noncoding mutations ; Pedigree ; PGAP3 ; Phosphatases ; Phosphorus Metabolism Disorders - genetics ; Phosphorus Metabolism Disorders - pathology ; Polymorphism, Single Nucleotide ; Receptors, Cell Surface - genetics ; RNA, Messenger - genetics ; Sequence Analysis, DNA - methods ; Young Adult
    ISSN: 1059-7794
    E-ISSN: 1098-1004
    Source: Hellenic Academic Libraries Link
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  • 10
    Language: English
    In: Clinical genetics, 2020-11, Vol.98 (5), p.468-476
    Description: PIGT is one of over 29 glycosylphosphatidylinositol biosynthesis defect genes. Mutations cause genetically determined disorders characterized mainly by epilepsy with fever‐sensitivity, central hypotonia, psychomotor delay and congenital malformations. The disease is known as multiple congenital anomalies‐hypotonia‐seizures syndrome 3 (MCAHS3) or glycosylphosphatidylinositol biosynthesis defect‐7. Twenty‐eight cases have been reported until today. We present seven novel Polish patients, all harboring 1582G〉A variant in a homozygous or compound heterozygous state which seems to cause a milder phenotype of the disease.
    Subject(s): antiepileptic drugs ; Biosynthesis ; Congenital defects ; Congenital diseases ; developmental encephalopathy with epilepsy ; Epilepsy ; Fever ; fever‐associated epilepsy ; Glycosylphosphatidylinositol ; glycosylphosphatidylinositol biosynthesis defects ; Phenotypes ; PIGT gene ; Seizures
    ISSN: 0009-9163
    E-ISSN: 1399-0004
    Source: Hellenic Academic Libraries Link
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