Atfa Sassi1, Sandra Lazaroski2, Gang Wu3, Stuart M Haslam3, Manfred Fliegauf2, Fethi Mellouli4, Turkan Patiroglu5, Ekrem Unal6, Mehmet Akif Ozdemir6, Zineb Jouhadi7, Khadija Khadir7, Leila Ben-Khemis1, Meriem Ben-Ali1, Imen Ben-Mustapha1, Lamia Borchani8, Dietmar Pfeifer9, Thilo Jakob10, Monia Khemiri11, A Charlotta Asplund12, Manuela O Gustafsson12, Karin E Lundin12, Elin Falk-Sörqvist13, Lotte N Moens13, Hatice Eke Gungor14, Karin R Engelhardt15, Magdalena Dziadzio15, Hans Stauss15, Bernhard Fleckenstein16, Rebecca Meier2, Khairunnadiya Prayitno2, Andrea Maul-Pavicic2, Sandra Schaffer2, Mirzokhid Rakhmanov2, Philipp Henneke2, Helene Kraus2, Hermann Eibel2, Uwe Kölsch17, Sellama Nadifi18, Mats Nilsson13, Mohamed Bejaoui4, Alejandro A Schäffer19, C I Edvard Smith12, Anne Dell3, Mohamed-Ridha Barbouche1, Bodo Grimbacher20. 1. Laboratory of Immunopathology, Vaccinology and Molecular Genetics, Pasteur Institute of Tunis and University Tunis El Manar, Tunis, Tunisia. 2. Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany. 3. Department of Life Sciences, Imperial College London, London, United Kingdom. 4. Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia. 5. Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey; Department of Pediatrics, Division of Pediatric Immunology, Faculty of Medicine, Erciyes University, Kayseri, Turkey. 6. Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey. 7. Department of Pediatric Infectious Diseases, CHU IBN ROCHD, Hassan II University, Casablanca, Morocco. 8. Laboratory of Venoms and Therapeutic Molecules, Institut Pasteur de Tunis, Tunis, Tunisia. 9. Department of Medicine I, Specialties: Hematology, Oncology, and Stem-Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany. 10. Allergy Research Group, Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany. 11. Pediatrics Department A, Children's Hospital of Tunis, Tunis, Tunisia. 12. Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden. 13. Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden. 14. Department of Pediatrics, Division of Pediatric Immunology, Faculty of Medicine, Erciyes University, Kayseri, Turkey. 15. Royal Free Hospital, Institute of Immunity & Transplantation, University College London, London, United Kingdom. 16. Institute of Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 17. Division of Immunology, Labor Berlin and Institute of Medical Immunology, Charité, Campus Virchow Klinikum, Berlin, Germany. 18. Department of Genetics, Hassan II University, Casablanca, Morocco. 19. National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md. 20. Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany; Royal Free Hospital, Institute of Immunity & Transplantation, University College London, London, United Kingdom. Electronic address: bodo.grimbacher@uniklinik-freiburg.de.
Abstract
BACKGROUND: Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. OBJECTIVE: We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. METHODS: After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. RESULTS: Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. CONCLUSION: Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype. Published by Mosby, Inc.
n class="abstract_title">BACKGROUND: Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. OBJECTIVE: We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. METHODS: After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. RESULTS: Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. CONCLUSION: Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype. Published by Mosby, Inc.
Entities:
Keywords:
Hyper-IgE syndrome; Staphylococcus aureus; dedicator of cytokinesis 8; glycosylation; phosphoglucomutase 3; signal transducer and activator of transcription 3
Authors: Y Wang; J Tan; M Sutton-Smith; D Ditto; M Panico; R M Campbell; N M Varki; J M Long; J Jaeken; S R Levinson; A Wynshaw-Boris; H R Morris; D Le; A Dell; H Schachter; J D Marth Journal: Glycobiology Date: 2001-12 Impact factor: 4.313
Authors: Kylie T Greig; Jennifer Antonchuk; Donald Metcalf; Phillip O Morgan; Danielle L Krebs; Jian-Guo Zhang; Douglas F Hacking; Lars Bode; Lorraine Robb; Christian Kranz; Carolyn de Graaf; Melanie Bahlo; Nicos A Nicola; Stephen L Nutt; Hudson H Freeze; Warren S Alexander; Douglas J Hilton; Benjamin T Kile Journal: Mol Cell Biol Date: 2007-06-04 Impact factor: 4.272
Authors: Cristina Woellner; E Michael Gertz; Alejandro A Schäffer; Macarena Lagos; Mario Perro; Erik-Oliver Glocker; Maria C Pietrogrande; Fausto Cossu; José L Franco; Nuria Matamoros; Barbara Pietrucha; Edyta Heropolitańska-Pliszka; Mehdi Yeganeh; Mostafa Moin; Teresa Español; Stephan Ehl; Andrew R Gennery; Mario Abinun; Anna Breborowicz; Tim Niehues; Sara Sebnem Kilic; Anne Junker; Stuart E Turvey; Alessandro Plebani; Berta Sánchez; Ben-Zion Garty; Claudio Pignata; Caterina Cancrini; Jiri Litzman; Ozden Sanal; Ulrich Baumann; Rosa Bacchetta; Amy P Hsu; Joie N Davis; Lennart Hammarström; E Graham Davies; Efrem Eren; Peter D Arkwright; Jukka S Moilanen; Dorothee Viemann; Sujoy Khan; László Maródi; Andrew J Cant; Alexandra F Freeman; Jennifer M Puck; Steven M Holland; Bodo Grimbacher Journal: J Allergy Clin Immunol Date: 2010-02 Impact factor: 10.793
Authors: Ponnusamy Babu; Simon J North; Jihye Jang-Lee; Sara Chalabi; Kathryn Mackerness; Sean R Stowell; Richard D Cummings; Sara Rankin; Anne Dell; Stuart M Haslam Journal: Glycoconj J Date: 2009-11 Impact factor: 2.916
Authors: Karin R Engelhardt; Michael E Gertz; Sevgi Keles; Alejandro A Schäffer; Elena C Sigmund; Cristina Glocker; Shiva Saghafi; Zahra Pourpak; Ruben Ceja; Atfa Sassi; Laura E Graham; Michel J Massaad; Fethi Mellouli; Imen Ben-Mustapha; Monia Khemiri; Sara Sebnem Kilic; Amos Etzioni; Alexandra F Freeman; Jens Thiel; Ilka Schulze; Waleed Al-Herz; Ayse Metin; Özden Sanal; Ilhan Tezcan; Mehdi Yeganeh; Tim Niehues; Gregor Dueckers; Sebastian Weinspach; Turkan Patiroglu; Ekrem Unal; Majed Dasouki; Mustafa Yilmaz; Ferah Genel; Caner Aytekin; Necil Kutukculer; Ayper Somer; Mehmet Kilic; Ismail Reisli; Yildiz Camcioglu; Andrew R Gennery; Andrew J Cant; Alison Jones; Bobby H Gaspar; Peter D Arkwright; Maria C Pietrogrande; Zeina Baz; Salem Al-Tamemi; Vassilios Lougaris; Gerard Lefranc; Andre Megarbane; Jeannette Boutros; Nermeen Galal; Mohamed Bejaoui; Mohamed-Ridha Barbouche; Raif S Geha; Talal A Chatila; Bodo Grimbacher Journal: J Allergy Clin Immunol Date: 2015-02-25 Impact factor: 10.793
Authors: Marcello Del Corvo; Mario Luini; Alessandra Stella; Giulio Pagnacco; Paolo Ajmone-Marsan; John L Williams; Giulietta Minozzi Journal: Mamm Genome Date: 2017-09-01 Impact factor: 2.957
Authors: Asbjørg Stray-Pedersen; Hanne Sørmo Sorte; Pubudu Samarakoon; Tomasz Gambin; Ivan K Chinn; Zeynep H Coban Akdemir; Hans Christian Erichsen; Lisa R Forbes; Shen Gu; Bo Yuan; Shalini N Jhangiani; Donna M Muzny; Olaug Kristin Rødningen; Ying Sheng; Sarah K Nicholas; Lenora M Noroski; Filiz O Seeborg; Carla M Davis; Debra L Canter; Emily M Mace; Timothy J Vece; Carl E Allen; Harshal A Abhyankar; Philip M Boone; Christine R Beck; Wojciech Wiszniewski; Børre Fevang; Pål Aukrust; Geir E Tjønnfjord; Tobias Gedde-Dahl; Henrik Hjorth-Hansen; Ingunn Dybedal; Ingvild Nordøy; Silje F Jørgensen; Tore G Abrahamsen; Torstein Øverland; Anne Grete Bechensteen; Vegard Skogen; Liv T N Osnes; Mari Ann Kulseth; Trine E Prescott; Cecilie F Rustad; Ketil R Heimdal; John W Belmont; Nicholas L Rider; Javier Chinen; Tram N Cao; Eric A Smith; Maria Soledad Caldirola; Liliana Bezrodnik; Saul Oswaldo Lugo Reyes; Francisco J Espinosa Rosales; Nina Denisse Guerrero-Cursaru; Luis Alberto Pedroza; Cecilia M Poli; Jose L Franco; Claudia M Trujillo Vargas; Juan Carlos Aldave Becerra; Nicola Wright; Thomas B Issekutz; Andrew C Issekutz; Jordan Abbott; Jason W Caldwell; Diana K Bayer; Alice Y Chan; Alessandro Aiuti; Caterina Cancrini; Eva Holmberg; Christina West; Magnus Burstedt; Ender Karaca; Gözde Yesil; Hasibe Artac; Yavuz Bayram; Mehmed Musa Atik; Mohammad K Eldomery; Mohammad S Ehlayel; Stephen Jolles; Berit Flatø; Alison A Bertuch; I Celine Hanson; Victor W Zhang; Lee-Jun Wong; Jianhong Hu; Magdalena Walkiewicz; Yaping Yang; Christine M Eng; Eric Boerwinkle; Richard A Gibbs; William T Shearer; Robert Lyle; Jordan S Orange; James R Lupski Journal: J Allergy Clin Immunol Date: 2016-07-16 Impact factor: 10.793
Authors: Asbjørg Stray-Pedersen; Paul H Backe; Hanne S Sorte; Lars Mørkrid; Niti Y Chokshi; Hans Christian Erichsen; Tomasz Gambin; Katja B P Elgstøen; Magnar Bjørås; Marcin W Wlodarski; Marcus Krüger; Shalini N Jhangiani; Donna M Muzny; Ankita Patel; Kimiyo M Raymond; Ghadir S Sasa; Robert A Krance; Caridad A Martinez; Shirley M Abraham; Carsten Speckmann; Stephan Ehl; Patricia Hall; Lisa R Forbes; Else Merckoll; Jostein Westvik; Gen Nishimura; Cecilie F Rustad; Tore G Abrahamsen; Arild Rønnestad; Liv T Osnes; Torstein Egeland; Olaug K Rødningen; Christine R Beck; Eric A Boerwinkle; Richard A Gibbs; James R Lupski; Jordan S Orange; Ekkehart Lausch; I Celine Hanson Journal: Am J Hum Genet Date: 2014-06-12 Impact factor: 11.025