Activity of phosphomannomutase 2 in patients with suspected congenital disorder of glycosylation
Authors:
H. Hansíková; N. Ondrušková; T. Honzík; K. Veselá; E. Horová; Š. Švecová; M. Tesařová; J. Zeman
Authors‘ workplace:
Klinika dětského a dorostového lékařství, 1. lékařská fakulta Univerzity Karlovy a Všeobecná fakultní nemocnice v Praze
Published in:
Klin. Biochem. Metab., 24, 2016, No. 2, p. 67-74
Overview
Objective:
Aim of study was to establish a method for determining the activity of phosphomannomutase 2 (PMM2) and phosphomannose isomerase (PMI) as a control enzyme in isolated lymphocytes and cultured skin fibroblasts and use it as a differential diagnostic step in a group of 18 patients with suspected CDG syndrome type I.
Design:
Original paper.
Settings:
Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague
Material and methods:
Cohort of samples consists of 16 isolated lymphocytes and 8 cultured skin fibroblasts lines from 18 patients from 15 unrelated families with high clinical suspicion for CDG syndrome type I. Group of controls consisted of 59 lymphocytes and 29 fibroblasts cell lines from disease free patients. Activities PMM2 and PMI were measured spectrophotometrically at 37 °C as the reduction of NADP+ to NADPH at 340 nm.
Results:
Statistically significant correlation between activity of PMM2 and PMI and age or gender in lymphocytes or cultured fibroblasts was not found. PMM2 activity in lymphocytes in the control group was from 0.34 to 2.58 nmol/min/mg (2.5% to 97.5% percentile) and in fibroblasts from 0.44 to 9.0 nmol/min/mg. PMM2 activity in lymphocytes in the group of patients was low (0.02-0.18 nmol/min/mg, interquartile range, controls 0.73-1.42 nmol/min/mg, p <0.001). PMM2 activity in fibroblasts from patients was also low (0.2-0.66 nmol/min/mg, controls 1.06-3.17 nmol/min/mg, p<0.001). PMM2 / PMI ratio in patients was significantly decreased in both tissues (p<0.001). The diagnosis of PMM2-CDG was confirmed by finding of mutations in PMM2 gene in all 18 patients.
Conclusion:
Measurement of PMM2 activity in lymphocytes or cultured fibroblasts allows to quickly diagnose PMM2-CDG, the most common congenital disorder of glycosylation
Keywords:
congenital disorders of glycosylation (CDG), phosphomannomutase (PMM2), phosphomannose isomerase (PMI).
Sources
1. Schachter, H., Freeze, H. H. Glycosylation diseases: quo vadis? Biochim Biophys Acta. 2009, 1792 (9): p. 925-30
2. Hennet, T., Cabalzar, J. Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction. Trends Biochem Sci. 2015, 40 (7): p. 377-84.
3. Aebi, M., Helenius, A., Schenk, B. et al. Carbohydrate-deficient glycoprotein syndromes become congenital disorders of glycosylation: an updated nomenclature for CDG. First International Workshop on CDGS. Glycoconj J. 1999, 16 (11): p. 669-71.
4. Haeuptle, M. A., Hennet, T. Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. Hum Mutat. 2009, 30 (12): p. 1628-41.
5. Matthijs, G., Schollen, E., Pardon, E. et al. Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nature Genet. 1997, 16: p. 88-92.
6. Honzík, T., Malonová, E., Hansíková, H. et al. Congenital disorder of type Ia protein glycosylation: clinical, biochemical and molecular characteristics in 2 siblings with cerebellar hypoplasia. Cas. Lek. Cesk., 2003, 142 (5): p. 276-9.
7. Honzík, T., Magner, M., Krijt, J. et al. Clinical picture of S-adenosyl-homocysteine hydrolase deficiency resembles phosphomannomutase 2 deficiency. Mol. Genet. Metab., 2012, 107 (3): p. 611-3.
8. Matthijs, G., Schollen, E., Bjursell, C. et al. Mutations in PMM2 that cause congenital disorders of glycosyla-tion, type Ia (CDG-Ia). Hum Mutat. 2000, 16 (5): p. 386-94.
9. Thiel, C., Lübke, T., Matthijs, G., von Figura, K., Körner, C. Targeted disruption of the mouse phosphomannomutase 2 gene causes early embryonic lethality. Mol. Cell. Biol., 2006, 26 (15): p. 5615-20
10. Higashidani, A., Bode, L., Nishikawa, A., Freeze, H. H. Exogenous mannose does not raise steady state mannose-6-phosphate pools of normal or N-glycosy-lation-deficient human fibroblasts. Mol. Genet. Metab., 2009, 96 (4): p. 268-72
11. Van Schaftingen, E., Jaeken, J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett. 1995, 377: p. 318-320
12. Lowry, O. H., Rosebrough, N. J., Farr, A. L., Randall, R. J. Protein measurement with the folin phenol reagent. J Biol. Chem., 1951, 193: p. 265-275.
13. Jaeken, J., Artigas, J., Barone, R. et al. Phosphomannomutase deficiency is the main cause of carbohydrate-deficient glycoprotein syndrome with type I isoelectrofocusing pattern of serum sialotransferrins. J Inherit Metab. Dis., 1997, 20 (3): p. 447-9.
14. Westphal, V., Peterson, S., Patterson, M. et al. Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia. Genet. Med., 2001, 3 (6): p. 393-8.
15. Vega, A. I., Pérez-Cerdá, C., Abia, D. al. Expression analysis revealing destabilizing mutations in phosphomannomutase 2 deficiency (PMM2-CDG): expression analysis of PMM2-CDG mutations. J Inherit. Metab. Dis., 2011, 34 (4): p. 929-39.
16. Grünewald, S., Schollen, E., Van Schaftingen, E., Jaeken, J., Matthijs, G. High residual activity of PMM2 in patients’ fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency). Am. J Hum. Genet., 2001, 68 (2): p. 347-54.
17. Kjaergaard, S., Skovby, F., Schwartz, M. Carbohydrate-deficient glycoprotein syndrome type 1A.: expression and characterisation of wild type and mutant PMM2 in E. coli. Eur J Hum. Genet., 1999, 7 (8): p. 884-8
18. Fletcher, J. M., Matthijs, G., Jaeken, J., Van Schaftingen, E., Nelson, P. V. Carbohydrate-deficient glycoprotein syndrome: beyond the screen. J Inherit. Metab. Dis., 2000, 23 (4): p. 396-8.
Labels
Clinical biochemistry Nuclear medicine Nutritive therapistArticle was published in
Clinical Biochemistry and Metabolism
2016 Issue 2
Most read in this issue
- Quality, control and validation of glucometers and CGM systems. Status overview
- Postanalytical phase and interpretation of laboratory tests
- Activity of phosphomannomutase 2 in patients with suspected congenital disorder of glycosylation
- The verification of the applicability of NPHS2/SYNPO ratio for diagnosis of FSGS and MCD