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Disorders of vitamin B6 metabolism
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
In hypophosphatasia (see Chapter 105) and hyperphosphatasia, the transport of PLP across the cellular membrane is impaired, effectively resulting in intracellular PLP deficiency and, again, seizures. Although in these disorders seizures and intellectual disability can be part of the clinical picture, their major clinical manifestations include bone disease and symptoms of hypercalcemia (see Chapter 105; Figure 100.1; TNSALP deficiency). In hyperprolinemia type II, as in antiquitin deficiency [3], an intermediate accumulating because of the primary defect scavenges pyridoxal-phosphate leading to PLP deficiency (Figure 100.3). A similar mechanism is responsible for pyridoxal deficiency developing during treatment with the drugs isoniazid or penicillamine. In disorders involving the anchoring of glycosylphosphatidylinositol alkaline phosphatase cannot be anchored resulting in hyperphosphatasia and vitamin B6 responsive epilepsy [5]. Finally, mutations in PROSC were recently identified to also cause vitamin B6-dependent epilepsy because of disturbed intracellular PLP homeostasis [6]. Clinically, this disease presents in very similar fashion to PNPO deficiency (see Pyridoxal-phosphate dependent epilepsy [pyridox(am)ine-5′-phosphate oxidase deficiency] section below), with early and severe onset, often with fetal distress, untreated leading to severe acqured microcephaly and severe permanent handicap.
Simpson–Golabi–Behmel Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The GPC4 gene is situated adjacent to the 3' end of the GPC3 gene on chromosome Xq26.2. Composed of nine exons, GPC4 also encodes a glycosylphosphatidylinositol-linked cell surface heparan sulfate proteoglycan (glypican-4 or GPC4). Duplication of GPC4 exons 1–9 in the absence of a GPC3 pathogenic variant is associated with SGBS, while loss-of-function GPC4 variant is not.
Immunoglobulins
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
There are two very different FcγRIII structures. FcγRIIIA is a transmembrane glycoprotein with two extracellular Ig-like domains. The major portion, designated the α chain, forms a complex with a dimer of one or both of either the γ chain of the high-affinity IgE receptor (see below), or the homologous ζ chain of the T cell receptor CD3 complex (see Chapter 6). The possible forms are αγ2, αγ-ζ, or αζ2· No alleles and a single transcript of FcγRIIIA have been identified; this form of the receptor is expressed by monocytes and derivatives, NK cells, and the γδ subset of T cells (Chapter 6). FcγRIIIB is unique among Fc receptors in that it does not span the cell membrane; it is joined to the cell membrane via a glycosylphosphatidylinositol (GPI) link. Two allotypes of this receptor exist, called ΝΑ-1 and NA-2 (distinguished by anti-neutrophil autoantibodies); only one transcript has been described. FcγRIIIB is found only on neutrophils. This receptor has intermediate affinity for IgG. The functional correlates of these structural differences await clarification.
Myelin-associated proteins are potential diagnostic markers in patients with primary brain tumour
Published in Annals of Medicine, 2021
Olga M. Koper-Lenkiewicz, Anna J. Milewska, Joanna Kamińska, Karol Sawicki, Robert Chrzanowski, Justyna Zińczuk, Joanna Reszeć, Marzena Tylicka, Ewa Matuszczak, Joanna Matowicka-Karna, Zenon Mariak, Mariusz W. Mucha, Robert Pawlak, Violetta Dymicka-Piekarska
An unexpected result was the finding of some serum OMgp concentrations in both primary brain tumours (N = 11) and non-tumoural individuals (N = 7). This is interesting because according to the literature OMgp is exclusively expressed only within the central nervous system [6]. The primary structure of OMgp is composed of four domains. At the N-terminus there is 32 aa Cys-rich motif (CR), which is followed by a 7 ½ tandem Leucine-rich repeats (LRRs) of 24 aa each, and subsequently by a domain of 4 ½ repeats of 40 residues each rich in Ser/Thr. The COOH-terminus contains glycosylphosphatidylinositol (GPI) as a membrane anchor. Among proteins, the platelet glycoprotein Ib (GPIb) was found to be the most similar to OMgp. These two proteins share richly in CR and LRRs motifs, but also contain Ser/Thr-rich regions [22]. Moreover, Mikol et al. [22] showed the similarity between the GPIbαβ heterodimer gene and the OMgp gene, which indicates that these two proteins may also be related by gene structure. The possible cross-reactivity in the ELISA test between these two proteins could account for our current results. For this reason, the obtained results regarding OMgp concentrations will not be subjected to further discussion.
Advances in the creation of animal models of paroxysmal nocturnal hemoglobinuria
Published in Hematology, 2021
Paroxysmal nocturnal hemoglobinuria (PNH) is caused by a PIG-A gene mutation in hematopoietic stem cells. The predominant clinical manifestations are hemolytic anemia, thrombosis, and bone marrow failure [1]. PIG-A gene mutation on the X chromosome of hematopoietic stem cells leads to the dysfunction of glycosylphosphatidylinositol (GPI) synthesis and the deficiency of GPI anchor protein (GPI-AP) on the cell membrane [2,3]. Flow cytometry, the gold standard test for the clinical diagnosis of PNH, is used to detect GPI-APs such as CD55 and CD59, along with the application of FLAER test to detect GPI protein. Currently, the main treatments of PNH include controlling the onset of hemolysis, stimulating hematopoiesis, and preventing thrombosis. Recombinant human anti-complement 5 monoclonal antibodies have been used to significantly improve the prognosis of patients with PNH. However, since these drugs are not yet available in China, glucocorticoids remain the standard therapeutic agents. Glucocorticoids or monoclonal antibodies can reduce the complement-mediated lysis of PNH clones, thereby alleviating clinical symptoms such as hemolysis [4,5]. Elucidation of the pathogenesis of PNH has not advanced over the last decade, owing to the lack of representative cell lines and animal models. This limits the research and development of the targeted drugs. The relevant characteristics of the existing PNH animal models are summarized in this paper.
Targeting on glycosylation of mutant FLT3 in acute myeloid leukemia
Published in Hematology, 2019
Glycosylation is a modification occurring in post-translational proteins. The glycoproteins are involved in many key biological processes, including cell growth, differentiation and immune regulation [9]. Altered glycosylation has been found in inflammatory diseases and many types of cancer [10,11]. Glycosylation modification of proteins with the participation of a series of enzymes refers to the process of covalent binding of sugar chains to specific amino acid residues in proteins. Glycosylation of proteins is involved in cell recognition by affecting the spatial structure, localization and stability of new peptide chains. Abnormal glycosylation modification is closely related to the avoidance of surveillance and tumorigenesis [12,13]. Endoplasmic reticulum generates the initiation of many types of protein glycosylation, for example N-glycosylation, O-mannosylation, and glycosylphosphatidylinositol (GPI) anchor addition [13].