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Severe Congenital Neutropenia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The G6PC3 (glucose-6-phosphatase catalytic subunit 3) gene on chromosome 17q21.31 spans 5.6 kb with 6 exons and encodes the 346 aa, 38.7 kDa catalytic subunit of glucose-6-phosphatase (G6Pase). Located in the endoplasmic reticulum, G6Pase catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the final step of the gluconeogenic and glycogenolytic pathways. Homozygous or compound heterozygous G6PC3 mutations [e.g., c.130C>T (p.Phe44Ser, of Pakistani origin), c.210delC (p.Phe71SerfsTer46 or Ile70fsTer46, of Hispanic origin), c.758G>A (p.Arg253His. of Middle Eastern origin), c.778G>C (p.Gly260Arg, of European origin), c.829C>T (p.Gly277Ter, of European origin), c.935dupT (p.Asn313GlnfsTer74 or Asn313fs, of Iranian origin)] decrease cytoplasmic glucose and glucose-6-phosphate levels, which in turn induce GSK-3β and phosphorylation-mediated inactivation of the anti-apoptotic molecule Mcl-1, activate the endoplasmic reticulum stress mechanism, increase susceptibility to cellular apoptosis, and cause aberrant glycosylation of NADPH oxidase subunit, gp91phox, leading to deficits in neutrophil function, and a phenotypic continuum (nonsyndromic isolated SCN, classic G6PC3 deficiency [SCN plus cardiovascular and/or urogenital abnormalities], and severe G6PC3 deficiency [classic G6PC3 deficiency plus involvement of non-myeloid hematopoietic cell lines, additional extra-hematologic features, and pulmonary hypertension]) [16,17].
Clinical and Mutation Description of the First Iranian Cohort of Infantile Inflammatory Bowel Disease: The Iranian Primary Immunodeficiency Registry (IPIDR)
Published in Immunological Investigations, 2021
Farzaneh Rahmani, Elham Rayzan, Mohammad Reza Rahmani, Sepideh Shahkarami, Samaneh Zoghi, Arezoo Rezaei, Zahra Aryan, Mehri Najafi, Meino Rohlfs, Tim Jeske, Majid Aflatoonian, Zahra Chavoshzadeh, Fatemeh Farahmand, Farzaneh Motamed, Pejman Rohani, Hossein Alimadadi, Alireza Mahdaviani, Mahboubeh Mansouri, Marzieh Tavakol, Mirjam Vanderberg, Daniel Kotlarz, Christoph Klein, Nima Rezaei
Patients P11 to P14 were shown to have aberrancies in their immunologic work-up in form of reduced CD4, CD3 and/or CD8 + T cells, or CD19 + B cells counts. WES revealed a novel homozygous mutation in the zeta-chain-associated protein kinase (ZAP70) gene in P11, who presented with intractable diarrhea and recurrent oral thrush. We also revealed a novel missense mutation in the recombination-activating 1 (RAG1) in P12 [http://exac.broadinstitute.org/variant/11-36596710-C-T], and a novel missense mutation in DNA ligase 4 (LIG4) in P13 that had never been reported in association with EO-IBD before. Patient P14 had a possibly destructive missense mutation in the glucose-6-phosphatase catalytic subunit 3 (G6PC3) gene. She presented with intractable diarrhea, and refractory rectovaginal and rectoperineal fistula, along with atrial septal defect and congenital inguinal hernia, both requiring surgery early after birth, but had no apparent abnormalities in blood count.
Chronic neutropenia: how best to assess severity and approach management?
Published in Expert Review of Hematology, 2021
Jean Donadieu, Stephanie Frenz, Lauren Merz, Flore Sicre De Fontbrune, Gioacchino Andrea Rotulo, Blandine Beaupain, Martin Biosse-Duplan, Marie Audrain, Laure Croisille, Phil Ancliff, Christoph Klein, Christine Bellanné-Chantelot
In the last 3 years, new molecules have been adapted to the pathophysiology of the three genetic diseases and are now in clinical trials or evaluation. In CXCR4 WHIM syndrome, a CXCR4 subcutaneous inhibitor (plerixafor) has been shown to be efficacious [69,70] and is also proceeding in a clinical trial with mavorixafor, an oral compound [71]. Significant progress has also been made in glycogen storage disease type Ib and G6PC3 – (glucose-6-phosphatase catalytic subunit 3) deficiency neutropenia, which are related to a defect in the glucose-6-phosphatase enzyme. The mechanism of the neutropenia in both of these diseases was recently elucidated. In neutrophils, the transporter G6PT and the phosphatase G6PC3 collaborate to metabolize 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a phosphorylated analogue of glucose that otherwise accumulates into the neutrophils from these patients and intoxicates them due to powerful inhibition of the glucose phosphorylating enzyme hexokinase [72]. Therefore, G6PT transports not only glucose-6-phosphate, but also its structural analogue 1,5AG6P (i.e. 1,5-anhydroglucitol-6-phosphate), which is dephosphorylated by G6PC3 in the endoplasmic reticulum in 1,5AG (i.e. 1,5-anhydroglucitol), preventing its accumulation in neutrophils. When either G6PT (GSDIb patients) or G6PC3 (G6PC3-deficient patients) are deficient, 1,5AG6P accumulates in the neutrophils [72]. Modulating the concentration of 1,5AG in the blood of G6PC3-deficient mice [73] impacts the number of neutrophils. The precursor of the toxic metabolite (1,5-AG) is filtrated and then reabsorbed by sodium-glucose co-transporter (SGLT2). SGLT2 inhibitors, such as empagliflozin or dapagliflozin, which are commonly used clinically as anti-diabetic drugs to treat type 2 diabetes, inhibit the SGLT2 transporter and hence reabsorption of 1,5-AG and thus decrease the concentration of the toxic metabolite in the body [72]. These findings have a potential clinical impact because they allow, in G6PT – and G6PC3-deficient patients, the reversal of clinical manifestations of neutropenia and neutrophil dysfunction, as recently confirmed in four patients with GSDIb [74].