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Glucokinase mutations in pediatric patients with impaired fasting glucose

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Abstract

Aims

Our aim was to detect the frequency of glucokinase (GCK) gene mutations in a cohort of patients with impaired fasting glucose and to describe the clinical manifestations of identified variants. We also aimed at predicting the effect of the novel missense mutations by computational approach.

Methods

Overall 100 unrelated Italian families with impaired fasting glucose were enrolled and subdivided into two cohorts according to strict and to mild criteria for diagnosis of maturity-onset diabetes of the young (MODY). GCK gene sequencing was performed in all participants.

Results

Fifty-three Italian families with 44 different mutations affecting the GCK and co-segregating with the clinical phenotype of GCK/MODY were identified. All mutations were in heterozygous state. In Sample 1, GCK defects were found in 32/36 (88.9%) subjects selected with strict MODY diagnostic criteria, while in Sample 2 GCK defects were found in 21/64 (32.8%) subjects selected with mild MODY diagnostic criteria.

Conclusions

Our study enlarged the wide spectrum of GCK defects by adding 9 novel variants. The application of strict recruitment criteria resulted in 88.9% incidence of GCK/MODY, which confirmed it as the commonest form of MODY in the Italian population. In order to avoid misdiagnosis of GCK/MODY, it could be useful to perform molecular screening even if one or more clinical parameters for the diagnosis of MODY are missing. Computational analysis is useful to understand the effect of GCK defect on protein functionality, especially when the novel identified variant is a missense mutation and/or parents’ DNA is not available.

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References

  1. Owen K, Hattersley AT (2001) Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Pract Res Clin Endocrinol Metab 15:309–323

    Article  CAS  PubMed  Google Scholar 

  2. Fajans SS, Bell GI, Polonsky KS (2001) Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 345:971–980

    Article  CAS  PubMed  Google Scholar 

  3. Barrett TG (2007) Differential diagnosis of type 1 diabetes: Which genetic syndromes need to be considered? Pediatr Diabetes 8:15–23

    Article  PubMed  Google Scholar 

  4. Gao R, Liu Y, Gjesing AP, Hollensted M, Wan X, He S, Pedersen O, Yi X, Wang J, Hansen T (2014) Evaluation of a target region capture sequencing platform using monogenic diabetes as a study-model. BMC Genet 15:13

    Article  PubMed  PubMed Central  Google Scholar 

  5. Froguel P, Vaxillaire M, Sun F, Velho G, Zouali HM, Butel O, Lesage S, Vionnet N, Clément K, Fougerousse F, Tanizawa Y, Weissenbachparallel J, Beckmann JS, Lathrop GM, Passa PH, Permutt MA, Cohen D (1992) Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356:162–164

    Article  CAS  PubMed  Google Scholar 

  6. Neve B, Fernandez-Zapico ME, Ashkenazi-Katalan V, Dina C, Hamid YH, Joly E, Vaillant E, Benmezroua Y, Durand E, Bakaher N, Delannoy V, Vaxillaire M, Cook T, Dallinga-Thie GM, Jansen H, Charles MA, Clément K, Galan P, Hercberg S, Helbecque N, Charpentier G, Prentki M, Hansen T, Pedersen O, Urrutia R, Melloul D, Froguel P (2005) Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. Proc Natl Acad Sci USA 102:4807–4812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Raeder H, Johansson S, Holm PI, Haldorsen IS, Mas E, Sbarra V, Nermoen I, Eide SA, Grevle L, Bjorkhaug L, Sagen JV, Aksnes L, Sovik O, Lombardo D, Molven A, Njolstad PR (2006) Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet 38:54–62

    Article  CAS  PubMed  Google Scholar 

  8. Plengvidhya N, Kooptiwut S, Songtawee N, Doi A, Furuta H, Nishi M, Nanjo K, Tantibhedhyangkul W, Boonyasrisawat W, Yenchitsomanus P, Doria A, Banchuin N (2007) PAX4 mutations in Thais with maturity onset diabetes of the young. J Clin Endocr Metab 92:2821–2826

    Article  CAS  PubMed  Google Scholar 

  9. Borowiec M, Liew CW, Thompson R, Boonyasrisawat W, Hu J, Mlynarski WM, El Khattabi I, Kim SH, Marselli L, Rich SS, Krolewski AS, Bonner-Weir S, Sharma A, Sale M, Mychaleckyj JC, Kulkarni RN, Doria A (2009) Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. PNAS 25:14460–14465

    Article  Google Scholar 

  10. Colombo C, Porzio O, Liu M, Massa O, Vasta M, Salardi S, Beccaria L, Monciotti C, Toni S, Pedersen O, Hansen T, Federici L, Pesavento R, Cadario F, Federici G, Ghirri P, Arvan P, Iafusco D, Barbetti F (2008) Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. J Clin Invest 118:2148–2156

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Boesgaard TW, Pruhova S, Andersson EA, Cinek O, Obermannova B, Lauenborg J, Damm P, Bergholdt R, Pociot F, Pisinger C, Barbetti F, Lebl J, Pedersen O, Hansen T (2010) Further evidence that mutations in INS can be a rare cause of maturity onset diabetes of the young (MODY). BMC Med Genet 11:42

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bowman P, Flanagan SE, Edghill EL, Damhuis A, Shepherd MH, Paisey R, Hattersley AT, Ellard S (2012) Heterozygous ABCC8 mutations are a cause of MODY. Diabetologia 55:123–127

    Article  CAS  PubMed  Google Scholar 

  13. Bonnefond A, Philippe J, Durand E, Dechaume A, Huyvaert M, Montagne L, Marre M, Balkau B, Fajardy I, Vambergue A, Vatin V, Delplanque J, Le Guilcher D, De Graeve F, Lecoeur C, Sand O, Vaxillaire M, Froguel P (2012) Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS ONE 7:e37423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lorini R, Klersy C, d’Annunzio G, Massa O, Minuto N, Iafusco D, Bellannè-Chantelot C, Frongia AP, Toni S, Meschi F, Cerutti F, Barbetti F (2009) Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families. Diabet Care 10:1864–1866

    Article  Google Scholar 

  15. Delvecchio M, Mozzillo E, Salzano G, Iafusco D, Frontino G, Patera PI, Rabbone I, Cherubini V, Grasso V, Tinto N, Giglio S, Contreas G, Di Paola R, Salina A, Cauvin V, Tumini S, d’Annunzio G, Iughetti L, Mantovani V, Maltoni G, Toni S, Marigliano M, Barbetti F (2017) Monogenic diabetes accounts for 6.3% of cases referred to 15 Italian pediatric diabetes centers during 2007–2012. J Clin Endocrinol Metab. doi:10.1210/jc.2016-2490

    Google Scholar 

  16. Velho G, Froguel P, Clement K, Pueyo ME, Rakotoambinina B, Zouali H, Passa P, Cohen D, Robert JJ (1992) Primary pancreatic beta-cell secretory defect caused by mutations in the glucokinase in kindreds of maturity onset diabetes of the young. Lancet 340:444–448

    Article  CAS  PubMed  Google Scholar 

  17. Njølstad PR, Søvik O, Cuesta-Muñoz A, Bjørkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI (2001) Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 344:1588–1592

    Article  PubMed  Google Scholar 

  18. Rubio-Cabezas O, Hattersley AT, Njølstad PR, Mlynarski W, Ellard S, White N, Chi DV, Craig ME, International Society for Pediatric and Adolescent Diabetes, ISPAD Clinical Practice Consensus Guidelines (2014) The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabet 20:47–64

    Article  Google Scholar 

  19. Stride A, Vaxillaire M, Tuomi T, Barbetti F, Njølstad PR, Hansen T, Costa A, Conget I, Pedersen O, Søvik O, Lorini R, Groop L, Froguel P, Hattersley AT (2000) The genetic abnormality in beta cell determines the response to an oral glucose load. Diabetologia 45:427–435

    Article  Google Scholar 

  20. Tinto N, Zagari A, Capuano M, De Simone A, Capobianco V, Daniele G, Giugliano M, Spadaro R, Franzese A, Sacchetti L (2008) Glucokinase gene mutations: structural and genotype-phenotype analyses in MODY children from South Italy. PLoS ONE 4:1870–1878

    Article  Google Scholar 

  21. Gasperíková D, Tribble ND, Staník J, Hucková M, Misovicová N, van de Bunt M, Valentínová L, Barrow BA, Barák L, Dobránsky R, Bereczková E, Michálek J, Wicks K, Colclough K, Knight JC, Ellard S, Klimes I, Gloyn AL (2009) Identification of a novel β-cell glucokinase (GCK) promoter mutation (−71G > C) that modulates GCK gene expression through loss of allele-specific Sp1 binding causing mild fasting hyperglycemia in humans. Diabetes 58:1929–1935

    Article  PubMed  PubMed Central  Google Scholar 

  22. Sali A, Blundell TL (1993) Comparative protein modeling by satisfaction of spatial restraints. J Mol Biol 234:779–815

    Article  CAS  PubMed  Google Scholar 

  23. Kamata K, Mitsuya M, Nishimura T, Eiki J, Nagata Y (2004) Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure 12:429–438

    Article  CAS  PubMed  Google Scholar 

  24. Prisco F, Iafusco D, Franzese A, Sulli N, Barbetti F (2000) MODY 2 presenting as neonatal hyperglycaemia: A need to reshape the definition of “neonatal diabetes”? Diabetologia 43:1331–1332

    Article  CAS  PubMed  Google Scholar 

  25. Salina A, Aloi C, Pasquali L, Mascagni A, Cassanello M, Tallone R, Lugani F, Lorini R, d’Annunzio G (2012) Comment on: clinical application of best practice guidelines for genetic diagnosis of MODY2. Diabet Res Clin Pract 95:e29–e30

    Article  CAS  Google Scholar 

  26. Zhang J, Li C, Shi T, Chen K, Shen X, Jiang H (2009) Lys169 of human glucokinase is a determinant for glucose phosphorylation: implication for the atomic mechanism of glucokinase catalysis. PLoS ONE 4:6304–6316

    Article  Google Scholar 

  27. Mahalingam B, Cuesta-Munoz A, Davis EA, Matschinsky FM, Harrison RW, Weber IT (1999) Structural model of human glucokinase in complex with glucose and ATP: implications for the mutants that cause hypo- and hyperglycemia. Diabetes 48:1698–1705

    Article  CAS  PubMed  Google Scholar 

  28. Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3:285–298

    Article  CAS  PubMed  Google Scholar 

  29. Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S, Gloyn AL (2009) Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat 30:1512–1526

    Article  CAS  PubMed  Google Scholar 

  30. Massa O, Meschi F, Cuesta-Munoz A, Caumo A, Cerutti F, Toni S, Cherubini V, Guazzarotti L, Sulli N, Matschinsky FM, Lorini R, Iafusco D, Barbetti F (2001) High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI. Diabetologia 44:898–905

    Article  CAS  PubMed  Google Scholar 

  31. Stanik J, Dusatkova P, Cinek O, Valentinova L, Huckova M, Skopkova M, Dusatkova L, Stanikova D, Pura M, Klimes I, Lebl J, Gasperikova D, Pruhova S (2014) De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed. Diabetologia 57:480–484

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Prof. Gianmarco Ghiggeri, MD. We also thank Anna Capurro for English language revision of the manuscript.

Authors’ contributions

AS and CA conceived and designed the experiments, performed molecular investigation, analyzed data, performed computational analysis, drafted and revised the manuscript, and approved the final manuscript as submitted. NM, RT made clinical diagnosis. FL analyzed data. AM performed β-cell autoantibody detection test. OM, MC revised the manuscript. MM critically reviewed the manuscript and approved the final manuscript as submitted. GdA made clinical diagnosis, conceptualized and designed the study, critically reviewed the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Author notes

  1. C. Aloi and A. Salina have been equally contributed to this study.

Authors and Affiliations

  1. Laboratory of Diabetology - Laboratory for the Study of Inborn Errors of Metabolism, Istituto Giannina Gaslini, Genoa, Italy

    C. Aloi & A. Salina

  2. Pediatric Clinic, Regional Center of Diabetes, Istituto Giannina Gaslini, Via G. Gaslini, 5, 16147, Genoa, Italy

    N. Minuto, R. Tallone & G. d’Annunzio

  3. Laboratory of Pathophysiology of Uremia, Istituto Giannina Gaslini, Genoa, Italy

    F. Lugani

  4. Laboratory for the Study of Inborn Errors of Metabolism, DINOGMI, University of Genoa, Genoa, Italy

    A. Mascagni

  5. Laboratory for the Study of Inborn Errors of Metabolism, Istituto Giannina Gaslini, Genoa, Italy

    O. Mazza & M. Cassanello

  6. Pediatric Clinic, University of Genoa, Genoa, Italy

    M. Maghnie

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  1. C. Aloi
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  2. A. Salina
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  10. G. d’Annunzio
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Corresponding author

Correspondence to G. d’Annunzio.

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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

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Informed consent was obtained from participant for being included in the study.

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Aloi, C., Salina, A., Minuto, N. et al. Glucokinase mutations in pediatric patients with impaired fasting glucose. Acta Diabetol 54, 913–923 (2017). https://doi.org/10.1007/s00592-017-1021-y

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  • DOI: https://doi.org/10.1007/s00592-017-1021-y

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