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Letters to the Editor
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Figure 3. Localization of the GNE mutations associated with thrombocytopenia and three-dimensional structure of the GNE enzyme. (A) Among the 15 muta- tions (Online Supplementary Table S3), the 7 associated with myopathy are indicated below the schematic representation of the protein structure; the other 8 are depicted above the protein (in red, the novel mutations reported in this paper). All the mutations identified in patients are in a homozygous state except those represented in matched colored boxes that are heterozygous biallelic GNE mutations found in a single patient. H188Y and N550S (light grey boxes) are homozygous mutations identified in the same patient. UDP-GlcNAc 2-epimerase: UDP-N-acetylglucosamine 2-epimerase; ManNAc kinase: N-acetylman- nosamine; NH2: NH2-terminus; COOH: COOH-terminus; RUF: a region with unknown function; NES: putative nuclear export signal; AS: allosteric site. Nomenclature of mutations was referred to the NM_001128227.3 transcript. (B) The overall structure (left) and the zoom of the enzymatic pocket (right) of GNE. The side chains of the positions affected by the mutations discussed in this article are explicitly indicated. The structure (Protein Data Bank [PDB] entry 2yhy) corresponds to the GNE complex with ManNAc and ADP. The structure was analyzed by PyMOL and MOLMOL graphic support tools. The degree of exposure of the residues affected by mutations was established by DSSP (Define Secondary Structure of Proteins) analysis.
genes, such as ANKRD18A, FRMPD1, FLNB, PRKACG, have been reported in other cases.2,3,5,14 However, their potential impact was not further investigated, except for p.Ile74Met in PRKACG, whose functional studies demon- strated its effect in thrombocytopenia.14
In summary, although the role of GNE mutations is well-documented in GNE myopathy and sialuria, we identified two novel GNE variants, which together with a few other mutations reported in the literature could explain thrombocytopenia and extend the clinical phe- notype of the GNE defects. In both patients, as well as in those of families F3 and F5 from a literature review, severe thrombocytopenia was reported since the first days of life, when the differential diagnosis of thrombo- cytopenia was broad and included thrombocytopenia secondary to sepsis and critical care, neonatal allo- and auto-immune thrombocytopenia, or ITP, such as congen- ital amegakaryocytic thrombocytopenia.15 Therefore, evaluating the sialotransferrin profile in patients with suspected inherited thrombocytopenia, large platelets and increased reticulated fraction might provide an important diagnostic clue.
Roberta Bottega,1* Antonio Marzollo,2,3* Maddalena Marinoni,4 Emmanouil Athanasakis,1 Ilaria Persico,5,6 Anna Monica Bianco,1 Michela Faleschini,1 Erica Valencic,1
Daniela Simoncini,4 Linda Rossini,2 Fabio Corsolini,7 Martina La Bianca,1 Giuseppe Robustelli,4 Maria Gabelli,2 Massimo Agosti,4 Alessandra Biffi,2 Paolo Grotto,8 Valeria Bozzi,9 Patrizia Noris,9,10 Alberto B. Burlina,11 Adamo Pio d'Adamo,1,5 Alberto Tommasini,1,5 Flavio Faletra,1 Annalisa Pastore12,13 and Anna Savoia1,5
1Istitute for Maternal and Child Health – IRCCS Burlo Garofolo, Trieste, Italy; 2Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy; 3Fondazione Città della Speranza, Istituto di Ricerca Pediatrica, Padua, Italy; 4Maternal and Child Department, F. Del Ponte Hospital, Varese, Italy; 5Department of Medical Sciences, University of Trieste, Trieste, Italy; 6Department of Genetics and Microbiology, Universitat Autonoma de Barcelona, Barcelona, Spain; 7LABSIEM - Laboratory for the Study of Inborn Errors of Metabolism, Pediatric Clinic and Endocrinology, Istituto Giannina Gaslini, Genova, Italy; 8Pediatric Department, Hospital of Treviso - Oderzo, Treviso, Italy; 9Biotechnology Research Laboratories, IRCCS Policlinico San Matteo Foundation, Pavia, Italy; 10Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy; 11Division of Inherited Metabolic Diseases, Regional Center for Expanded Neonatal Screening Department of Women and Children’s Health, University Hospital of Padova, Padova, Italy; 12King’s College London, Department of Clinical Neuroscience, Denmark Hill Campus, London, UK and 13European Synchrotron Radiation Facility 71, Grenoble, France
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