A new compound heterozygosis for inactivating mutations in the glucokinase gene as cause of permanent neonatal diabetes mellitus (PNDM) in double-first cousins

Diabetology & Metabolic Syndrome

Sofia Helena Valente De Lemos-Marini¹  Gil Guerra-Júnior¹  Walter José Minicucci³  Maria Fernanda Vanti Macedo Paulino⁴  Maricilda Palandi De Mello²  Adriana Mangue Esquiaveto-Aun¹ 

[1] Center for Investigation in Pediatrics (CIPED), FCM, UNICAMP, Campinas, Brazil;Center of Molecular Biology and Genetic Engineering (CBMEG), UNICAMP, Campinas, Brazil;Division of Endocrinology, Department of Clinical Medicine, FCM, UNICAMP, Campinas, Brazil;Department of Pediatrics, School of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, SP, Brazil

关键词: GCK;    Glucokinase;    MODY;    PNDM;    Permanent neonatal diabetes mellitus;   

Others  :  1234354
DOI  :  10.1186/s13098-015-0101-9

 received in 2015-07-03, accepted in 2015-11-05,  发布年份 2015

【 摘 要 】

Background

Permanent neonatal diabetes mellitus (PNDM) is a rare disorder, characterized by uncontrolled hyperglycemia diagnosed during the first 6 months of life. In general, PNDM has a genetic origin and most frequently it results from heterozygous mutations in KCNJ11, INS and ABCC8 genes. Homozygous or compound heterozygous inactivating mutations in GCK gene as cause of PNDM are rare. In contrast, heterozygosis for GCK inactivating mutations is frequent and results in the maturity-onset diabetes of young (MODY), manifested by a mild fasting hyperglycemia usually detected later in life. Therefore, as an autosomal recessive disorder, GCK-PNDM should be considered in families with history of glucose intolerance or MODY in first relatives, especially when consanguinity is suspected.

Results

Here we describe two patients born from non-consanguineous parents within a family. They presented low birth weight with persistent hyperglycemia during the first month of life. Molecular analyses for KCNJ11, INS, ABCC8 did not show any mutation. GCK gene sequencing, however, revealed that both patients were compound heterozygous for two missense combined in a novel GCK-PNDM genotype. The p.Asn254His and p.Arg447Gly mutations had been inherited from their mothers and fathers, respectively, as their mothers are sisters and their fathers are brothers. Parents had been later diagnosed as having GCK-MODY.

Conclusions

Mutations’ in silico analysis was carried out to elucidate the role of the amino acid changes on the enzyme structure. Both p.Asn254His and p.Arg447Gly mutations appeared to be quite damaging. This is the first report of GCK-PNDM in a Brazilian family.

【 授权许可】

   
2015 Esquiaveto-Aun et al.

【 图 表 】

Fig.1.

Fig.2.

Fig.3.

Fig.4.

【 参考文献 】

• [1]Edghill EL, Dix RJ, Flanagan SE, Bingley PJ, Hattersley AT, Ellard S, et al.: HLA genotyping supports a nonautoimmune etiology in patients diagnosed with diabetes under the age of 6 months. Diabetes 2006, 55(6):1895-1898.
• [2]Rubio-Cabezas O, Klupa T, Malecki MT, Consortium C: Permanent neonatal diabetes mellitus—the importance of diabetes differential diagnosis in neonates and infants. Eur J Clin Invest 2011, 41(3):323-333.
• [3]Stanik J, Gasperikova D, Paskova M, Barak L, Javorkova J, Jancova E, et al.: Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. J Clin Endocrinol Metab 2007, 92(4):1276-1282.
• [4]Slingerland AS, Shields BM, Flanagan SE, Bruining GJ, Noordam K, Gach A, et al.: Referral rates for diagnostic testing support an incidence of permanent neonatal diabetes in three European countries of at least 1 in 260,000 live births. Diabetologia 2009, 52(8):1683-1685.
• [5]Russo L, Iafusco D, Brescianini S, Nocerino V, Bizzarri C, Toni S, et al.: Permanent diabetes during the first year of life: multiple gene screening in 54 patients. Diabetologia 2011, 54(7):1693-1701.
• [6]Naylor RN, Greeley SAW, Bell GI, Philipson LH: Genetics and pathophysiology of neonatal diabetes mellitus. J Diab Invest 2011, 2(3):158-169.
• [7]Kanakatti Shankar R, Pihoker C, Dolan LM, Standiford D, Badaru A, Dabelea D, et al.: Permanent neonatal diabetes mellitus: prevalence and genetic diagnosis in the SEARCH for diabetes in youth study. Pediatr Diab 2013, 14(3):174-180.
• [8]Oriola J, Moreno F, Gutiérrez-Nogués A, León S, García-Herrero CM, Vincent O, et al.: Lack of glibenclamide response in a case of permanent neonatal diabetes caused by incomplete inactivation of glucokinase. JIMD Rep 2015, 20:21-26.
• [9]Gloyn AL, Ellard S, Shield JP, Temple IK, Mackay DJ, Polak M, et al.: Complete glucokinase deficiency is not a common cause of permanent neonatal diabetes. Diabetologia 2002, 45(2):290.
• [10]Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, et al.: Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med 1993, 328(10):697-702.
• [11]Njølstad PR, Søvik O, Cuesta-Muñoz A, Bjørkhaug L, Massa O, Barbetti F, et al.: Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 2001, 344(21):1588-1592.
• [12]Njølstad PR, Sagen JV, Bjørkhaug L, Odili S, Shehadeh N, Bakry D, et al.: Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes 2003, 52(11):2854-2860.
• [13]Turkkahraman D, Bircan I, Tribble ND, Akçurin S, Ellard S, Gloyn AL: Permanent neonatal diabetes mellitus caused by a novel homozygous (T168A) glucokinase (GCK) mutation: initial response to oral sulphonylurea therapy. J Pediatr 2008, 153(1):122-126.
• [14]Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A, et al.: Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 1998, 338(4):226-230.
• [15]Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S, et al.: Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat 2009, 30(11):1512-1526.
• [16]Iynedjian PB: Mammalian glucokinase and its gene. Biochem J 1993, 293(Pt 1):1-13.
• [17]Magnuson MA: Glucokinase gene structure. Functional implications of molecular genetic studies. Diabetes 1990, 39(5):523-527.
• [18]Matschinsky FM: Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics. Diabetes 2002, 51(Suppl 3):S394-S404.
• [19]Kamata K, Mitsuya M, Nishimura T, Eiki J, Nagata Y: Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure 2004, 12(3):429-438.
• [20]Hussain K: Mutations in pancreatic β-cell glucokinase as a cause of hyperinsulinaemic hypoglycaemia and neonatal diabetes mellitus. Rev Endocr Metab Disord. 2010, 11(3):179-183.
• [21]Gloyn AL, Noordam K, Willemsen MA, Ellard S, Lam WW, Campbell IW, et al.: Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations. Diabetes 2003, 52(9):2433-2440.
• [22]Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al.: Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004, 350(18):1838-1849.
• [23]Støy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, et al.: Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A. 2007, 104(38):15040-15044.
• [24]Babenko AP, Polak M, Cavé H, Busiah K, Czernichow P, Scharfmann R, et al.: Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006, 355(5):456-466.
• [25]Liu S, Ammirati MJ, Song X, Knafels JD, Zhang J, Greasley SE, et al.: Insights into mechanism of glucokinase activation: observation of multiple distinct protein conformations. J Biol Chem 2012, 287(17):13598-13610.
• [26]Ng PC, Henikoff S: Predicting the effects of amino acid substitutions on protein function. Annu Rev Genomics Hum Genet 2006, 7:61-80.
• [27]Pedelini L, Garcia-Gimeno MA, Marina A, Gomez-Zumaquero JM, Rodriguez-Bada P, López-Enriquez S, et al.: Structure-function analysis of the alpha5 and the alpha13 helices of human glucokinase: description of two novel activating mutations. Protein Sci 2005, 14(8):2080-2086.
• [28]Porter JR, Shaw NJ, Barrett TG, Hattersley AT, Ellard S, Gloyn AL: Permanent neonatal diabetes in an Asian infant. J Pediatr 2005, 146(1):131-133.
• [29]Rubio-Cabezas O, Díaz González F, Aragonés A, Argente J, Campos-Barros A: Permanent neonatal diabetes caused by a homozygous nonsense mutation in the glucokinase gene. Pediatr Diab 2008, 9(3 Pt 1):245-249.
• [30]Bennett K, James C, Mutair A, Al-Shaikh H, Sinani A, Hussain K: Four novel cases of permanent neonatal diabetes mellitus caused by homozygous mutations in the glucokinase gene. Pediatr Diab 2011, 12(3 Pt 1):192-196.
• [31]Wajda-Cuszlag M, Witkowski D, Piontek E, Wysocka-Mincewicz M, Borowiec M, Młynarski W, et al.: Glucokinase gene mutation as a causative factor of permanent neonatal diabetes mellitus. Pediatr Endocrinol Diab Metab 2012, 18(1):45-47.
• [32]Vaxillaire M, Samson C, Cavé H, Metz C, Froguel P, Polak M: Glucokinase gene mutations are not a common cause of permanent neonatal diabetes in France. Diabetologia 2002, 45(3):454-455.
• [33]Gloyn AL: Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. Hum Mutat 2003, 22(5):353-362.
• [34]Thomson KL, Gloyn AL, Colclough K, Batten M, Allen LI, Beards F, et al.: Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY). Hum Mutat 2003, 22(5):417.
• [35]Capuano M, Garcia-Herrero CM, Tinto N, Carluccio C, Capobianco V, Coto I, et al.: Glucokinase (GCK) mutations and their characterization in MODY2 children of southern Italy. PLoS ONE 2012, 7(6):e38906.
• [36]Shammas C, Neocleous V, Phelan MM, Lian LY, Skordis N, Phylactou LA: A report of 2 new cases of MODY2 and review of the literature: implications in the search for type 2 diabetes drugs. Metabolism 2013, 62(11):1535-1542.
• [37]Doliba NM, Fenner D, Zelent B, Bass J, Sarabu R, Matschinsky FM: Repair of diverse diabetic defects of β-cells in man and mouse by pharmacological glucokinase activation. Diab Obes Metab 2012, 14(Suppl 3):109-119.
• [38]Matschinsky FM: GKAs for diabetes therapy: why no clinically useful drug after two decades of trying? Trends Pharmacol Sci 2013, 34(2):90-99.