GPI-anchor and GPI-anchored protein expression in PMM2-CDG patients

Orphanet Journal of Rare Diseases

Maria L Lozano⁷  Jaak Jaeken¹  Vicente Vicente⁷  Antonia Miñano⁷  Encarna Guillén-Navarro³  Soren R Kristensen⁸  Teresa Sevivas⁵  Carmen Altisent⁴  Belen Pérez-Dueñas⁶  Irene Martínez-Martínez⁷  Roberto García-López²  Javier Corral⁷  Trinidad Hernández-Caselles²  Maria E de la Morena-Barrio⁷ 

[1] Center for Metabolic Diseases, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium;Departamento de Bioquímica, Biología Molecular B e Inmunología, Universidad de Murcia, Murcia, Spain;Unidad de Genética Médica. Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain;Unidad de Hemofilia, Hospital Universitario Vall d’Hebron, Barcelona, Spain;Hematology Department, Centro Hospitalar de Coimbra, Coimbra, Portugal;Departamento de Neurología Infantil, Hospital Sant Joan de Déu, Barcelona, Spain;Centro Regional de Hemodonación Servicio de Hematología y Oncología Médica. Hospital Universitario Morales Meseguer, Universidad de Murcia, Ronda de Garay S/N, 30003 Murcia, Spain;Hematology Department, Aalborg Hospital, Aalborg, Denmark

关键词: GPI-anchor and GPI-anchored proteins;    N-glycosylation defects;    PMM2-CDG;   

Others  :  863447
DOI  :  10.1186/1750-1172-8-170

 received in 2013-06-26, accepted in 2013-10-09,  发布年份 2013

【 摘 要 】

Background

Mutations in PMM2 impair phosphomannomutase-2 activity and cause the most frequent congenital disorder of glycosylation, PMM2-CDG. Mannose-1-phosphate, that is deficient in this disorder, is also implicated in the biosynthesis of glycosylphosphatidyl inositol (GPI) anchors.

Objective

To evaluate whether GPI-anchor and GPI-anchored proteins are defective in PMM2-CDG patients.

Methods

The expression of GPI-anchor and seven GPI-anchored proteins was evaluated by flow cytometry in different cell types from twelve PMM2-CDG patients. Additionally, neutrophil CD16 and plasma hepatic proteins were studied by Western blot. Transferrin glycoforms were evaluated by HPLC.

Results

Patients and controls had similar surface expression of GPI-anchor and most GPI-anchored proteins. Nevertheless, patients displayed a significantly diminished binding of two anti-CD16 antibodies (3G8 and KD1) to neutrophils and also of anti-CD14 (61D3) to monocytes. Interestingly, CD16 immunostaining and asialotransferrin levels significantly correlated with patients’ age. Analysis by flow cytometry of CD14 with MΦP9, and CD16 expression in neutrophils by Western blot using H-80 ruled out deficiencies of these antigens.

Conclusions

PMM2 mutations do not impair GPI-anchor or GPI-anchored protein expression. However, the glycosylation anomalies caused by PMM2 mutations might affect the immunoreactivity of monoclonal antibodies and lead to incorrect conclusions about the expression of different proteins, including GPI-anchored proteins. Neutrophils and monocytes are sensitive to PMM2 mutations, leading to abnormal glycosylation in immune receptors, which might potentially affect their affinity to their ligands, and contribute to infection. This study also confirms less severe hypoglycosylation defects in older PMM2-CDG patients.

【 授权许可】

   
2013 de la Morena-Barrio et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Hennet T: Diseases of glycosylation beyond classical congenital disorders of glycosylation. Biochim Biophys Acta 1820, 2012:1306-17.
• [2]Jaeken J: Congenital disorders of glycosylation (CDG): it’s (nearly) all in it! J Inherit Metab Dis 2011, 34:853-8.
• [3]Theodore M, Morava E: Congenital disorders of glycosylation: sweet news. Curr Opin Pediatr 2011, 23:581-7.
• [4]Jaeken J: Congenital disorders of glycosylation. Ann N Y Acad Sci 2010, 1214:190-8.
• [5]Van Schaftingen E, Jaeken J: Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett 1995, 377:318-20.
• [6]Matthijs G, Schollen E, Pardon E, Veiga-Da-Cunha M, Jaeken J, Cassiman JJ, Van Schaftingen E: Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nat Genet 1997, 16:88-92.
• [7]Jaeken J, Hennet T, Matthijs G, Freeze HH: CDG nomenclature: time for a change! Biochim Biophys Acta 2009, 1792:825-6.
• [8]Jaeken J, van Eijk HG, van der Heul C, Corbeel L, Eeckels R, Eggermont E: Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome. Clin Chim Acta 1984, 144:245-7.
• [9]Haeuptle MA, Hennet T: Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. Hum Mutat 2009, 30:1628-41.
• [10]Barone R, Aiello C, Race V, Morava E, Foulquier F, Riemersma M, Passarelli C, Concolino D, Carella M, Santorelli F, Vleugels W, Mercuri E, Garozzo D, Sturiale L, Messina S, Jaeken J, Fiumara A, Wevers RA, Bertini E, Matthijs G, et al.: DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy. Ann Neurol 2012, 72:550-8.
• [11]Arnoux JB, Boddaert N, Valayannopoulos V, Romano S, Bahi-Buisson N, Desguerre I, de Keyzer Y, Munnich A, Brunelle F, Seta N, Dautzenberg MD, de Lonlay P: Risk assessment of acute vascular events in congenital disorder of glycosylation type Ia. Mol Genet Metab 2008, 93:444-9.
• [12]Almeida A, Layton M, Karadimitris A: Inherited glycosylphosphatidyl inositol deficiency: a treatable CDG. Biochim Biophys Acta 2009, 1792:874-80.
• [13]Hill A, Kelly RJ, Hillmen P: Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013, 121:4985-96.
• [14]Quintana E, Navarro-Sastre A, Hernandez-Perez JM, Garcia-Villoria J, Montero R, Artuch R, Ribes A, Briones P: Screening for congenital disorders of glycosylation (CDG): transferrin HPLC versus isoelectric focusing (IEF). Clin Biochem 2009, 42:408-15.
• [15]de la Morena-Barrio ME, Sevivas TS, Martinez-Martinez I, Minano A, Vicente V, Jaeken J, Corral J: Congenital disorder of glycosylation (PMM2-CDG) in a patient with antithrombin deficiency and severe thrombophilia. J Thromb Haemost 2012, 10:2625-7.
• [16]Matthijs G, Schollen E, Van Schaftingen E, Cassiman JJ, Jaeken J: Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A. Am J Hum Genet 1998, 62:542-50.
• [17]Borowitz MJ, Craig FE, Digiuseppe JA, Illingworth AJ, Rosse W, Sutherland DR, Wittwer CT, Richards SJ: Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom 2010, 78:211-30.
• [18]Urbano-Ispizua A, Gaya A, Colado E, Lopez M, Arrizabalaga B, Vicente V, Orfao A, Villegas A, Vallejo C: Diagnosis and treatment of nocturnal paroxysmal hemoglobinuria. Med Clin (Barc) 2011, 136:121-7.
• [19]Hartmann RC, Jenkins DE Jr, Arnold AB: Diagnostic specificity of sucrose hemolysis test for paroxysmal nocturnal hemoglobinuria. Blood 1970, 35:462-75.
• [20]Wilcox LA, Ezzell JL, Bernshaw NJ, Parker CJ: Molecular basis of the enhanced susceptibility of the erythrocytes of paroxysmal nocturnal hemoglobinuria to hemolysis in acidified serum. Blood 1991, 78:820-9.
• [21]Perez-Oliva AB, Martinez-Esparza M, Vicente-Fernandez JJ, Corral-San MR, Garcia-Penarrubia P, Hernandez-Caselles T: Epitope mapping, expression and post-translational modifications of two isoforms of CD33 (CD33M and CD33m) on lymphoid and myeloid human cells. Glycobiology 2011, 21:757-70.
• [22]Starkel P, Sempoux C, Van DB V, Stevens M, De SC, Desager JP, Horsmans Y: CYP 3A proteins are expressed in human neutrophils and lymphocytes but are not induced by rifampicin. Life Sci 1999, 64:643-53.
• [23]Freeze HH: Understanding human glycosylation disorders: biochemistry leads the charge. J Biol Chem 2013, 288:6936-45.
• [24]Jaeken J, Matthijs G: Congenital disorders of glycosylation: a rapidly expanding disease family. Annu Rev Genomics Hum Genet 2007, 8:261-78.
• [25]Thomas LJ, DeGasperi R, Sugiyama E, Chang HM, Beck PJ, Orlean P, Urakaze M, Kamitani T, Sambrook JF, Warren CD: Functional analysis of T-cell mutants defective in the biosynthesis of glycosylphosphatidylinositol anchor. Relative importance of glycosylphosphatidylinositol anchor versus N-linked glycosylation in T-cell activation. J Biol Chem 1991, 266:23175-84.
• [26]Linssen M, Mohamed M, Wevers RA, Lefeber DJ, Morava E: Thrombotic complications in patients with PMM2-CDG. Mol Genet Metab 2013, 109:107-11.
• [27]Risitano AM: Paroxysmal nocturnal hemoglobinuria and other complement-mediated hematological disorders. Immunobiology 2012, 217:1080-7.
• [28]Van Geet C, Jaeken J, Freson K, Lenaerts T, Arnout J, Vermylen J, Hoylaerts MF: Congenital disorders of glycosylation type Ia and IIa are associated with different primary haemostatic complications. J Inherit Metab Dis 2001, 24:477-92.
• [29]Ravetch JV, Perussia B: Alternative membrane forms of Fc gamma RIII(CD16) on human natural killer cells and neutrophils. Cell type-specific expression of two genes that differ in single nucleotide substitutions. J Exp Med 1989, 170:481-97.
• [30]Fitzgerald KA, Rowe DC, Golenbock DT: Endotoxin recognition and signal transduction by the TLR4/MD2-complex. Microbes Infect 2004, 6:1361-7.
• [31]Willcocks LC, Lyons PA, Clatworthy MR, Robinson JI, Yang W, Newland SA, Plagnol V, McGovern NN, Condliffe AM, Chilvers ER, Adu D, Jolly EC, Watts R, Lau YL, Morgan AW, Nash G, Smith KG: Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake. J Exp Med 2008, 205:1573-82.
• [32]Echchannaoui H, Frei K, Letiembre M, Strieter RM, Adachi Y, Landmann R: CD14 deficiency leads to increased MIP-2 production, CXCR2 expression, neutrophil transmigration, and early death in pneumococcal infection. J Leukoc Biol 2005, 78:705-15.
• [33]Blank C, Smith LA, Hammer DA, Fehrenbach M, Delisser HM, Perez E, Sullivan KE: Recurrent infections and immunological dysfunction in congenital disorder of glycosylation Ia (CDG Ia). J Inherit Metab Dis 2006, 29:592.
• [34]Leonard J, Grunewald S, Clayton P: Diversity of congenital disorders of glycosylation. Lancet 2001, 357:1382-3.
• [35]Kimberly RP, Tappe NJ, Merriam LT, Redecha PB, Edberg JC, Schwartzman S, Valinsky JE: Carbohydrates on human Fc gamma receptors. Interdependence of the classical IgG and nonclassical lectin-binding sites on human Fc gamma RIII expressed on neutrophils. J Immunol 1989, 142:3923-30.
• [36]Edberg JC, Kimberly RP: Cell type-specific glycoforms of Fc gamma RIIIa (CD16): differential ligand binding. J Immunol 1997, 159:3849-57.
• [37]Stibler H, Holzbach U, Kristiansson B: Isoforms and levels of transferrin, antithrombin, alpha(1)-antitrypsin and thyroxine-binding globulin in 48 patients with carbohydrate-deficient glycoprotein syndrome type I. Scand J Clin Lab Invest 1998, 58:55-61.
• [38]Vermeer S, Kremer HP, Leijten QH, Scheffer H, Matthijs G, Wevers RA, Knoers NA, Morava E, Lefeber DJ: Cerebellar ataxia and congenital disorder of glycosylation Ia (CDG-Ia) with normal routine CDG screening. J Neurol 2007, 254:1356-8.
• [39]Sato Y, Endo T: Alteration of brain glycoproteins during aging. Geriatr Gerontol Int 2010, 10(Suppl 1):S32-S40.
• [40]Grunewald S: The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim Biophys Acta 2009, 1792:827-34.