All Title Author
Keywords Abstract

PLOS ONE  2012 

Whole-Exome Sequencing and High Throughput Genotyping Identified KCNJ11 as the Thirteenth MODY Gene

DOI: 10.1371/journal.pone.0037423

Full-Text   Cite this paper   Add to My Lib


Background Maturity-onset of the young (MODY) is a clinically heterogeneous form of diabetes characterized by an autosomal-dominant mode of inheritance, an onset before the age of 25 years, and a primary defect in the pancreatic beta-cell function. Approximately 30% of MODY families remain genetically unexplained (MODY-X). Here, we aimed to use whole-exome sequencing (WES) in a four-generation MODY-X family to identify a new susceptibility gene for MODY. Methodology WES (Agilent-SureSelect capture/Illumina-GAIIx sequencing) was performed in three affected and one non-affected relatives in the MODY-X family. We then performed a high-throughput multiplex genotyping (Illumina-GoldenGate assay) of the putative causal mutations in the whole family and in 406 controls. A linkage analysis was also carried out. Principal Findings By focusing on variants of interest (i.e. gains of stop codon, frameshift, non-synonymous and splice-site variants not reported in dbSNP130) present in the three affected relatives and not present in the control, we found 69 mutations. However, as WES was not uniform between samples, a total of 324 mutations had to be assessed in the whole family and in controls. Only one mutation (p.Glu227Lys in KCNJ11) co-segregated with diabetes in the family (with a LOD-score of 3.68). No KCNJ11 mutation was found in 25 other MODY-X unrelated subjects. Conclusions/Significance Beyond neonatal diabetes mellitus (NDM), KCNJ11 is also a MODY gene (‘MODY13’), confirming the wide spectrum of diabetes related phenotypes due to mutations in NDM genes (i.e. KCNJ11, ABCC8 and INS). Therefore, the molecular diagnosis of MODY should include KCNJ11 as affected carriers can be ideally treated with oral sulfonylureas.


[1]  Bonnefond A, Froguel P, Vaxillaire M (2010) The emerging genetics of type 2 diabetes. Trends Mol Med 16: 407.416
[2]  Bowman P, Flanagan SE, Edghill EL, Damhuis A, Shepherd MH (2012) Heterozygous ABCC8 mutations are a cause of MODY. Diabetologia 55: 123.127
[3]  Fajans SS, Bell GI (2011) MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care 34: 1878.1884
[4]  Vaxillaire M, Froguel P (2006) Genetic basis of maturity-onset diabetes of the young. Endocrinol Metab Clin North Am 35: 371–384, x.
[5]  Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ (2011) Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 12: 745.755
[6]  Bonnefond A, Durand E, Sand O, De Graeve F, Gallina S (2010) Molecular diagnosis of neonatal diabetes mellitus using next-generation sequencing of the whole exome. PLoS One 5: e13630.
[7]  Frayling TM, Lindgren CM, Chevre JC, Menzel S, Wishart M (2003) A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity. Diabetes 52: 872.881
[8]  Babenko AP, Aguilar-Bryan L, Bryan J (1998) A view of sur/KIR6.X, KATP channels. Annu Rev Physiol 60: 667.687
[9]  Babenko AP, Polak M, Cave H, Busiah K, Czernichow P (2006) Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 355: 456.466
[10]  Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE (2006) Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 355: 467.477
[11]  Iafusco D, Bizzarri C, Cadario F, Pesavento R, Tonini G (2011) No beta cell desensitisation after a median of 68 months on glibenclamide therapy in patients with KCNJ11-associated permanent neonatal diabetes. Diabetologia 54: 2736.2738
[12]  Rica I, Luzuriaga C, Perez de Nanclares G, Estalella I, Aragones A (2007) The majority of cases of neonatal diabetes in Spain can be explained by known genetic abnormalities. Diabet Med 24: 707.713
[13]  Edghill EL, Gloyn AL, Goriely A, Harries LW, Flanagan SE (2007) Origin of de novo KCNJ11 mutations and risk of neonatal diabetes for subsequent siblings. J Clin Endocrinol Metab 92: 1773.1777
[14]  Kochar IP, Kulkarni KP (2010) Transient Neonatal Diabetes due to Kcnj11 Mutation. Indian Pediatr 47: 359.360
[15]  Flanagan SE, Patch AM, Mackay DJ, Edghill EL, Gloyn AL (2007) Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes 56: 1930.1937
[16]  Girard CA, Shimomura K, Proks P, Absalom N, Castano L (2006) Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes. Pflugers Arch 453: 323.332
[17]  Stoy J, Greeley SA, Paz VP, Ye H, Pastore AN (2008) Diagnosis and treatment of neonatal diabetes: a United States experience. Pediatr Diabetes 9: 450.459
[18]  Landau Z, Wainstein J, Hanukoglu A, Tuval M, Lavie J (2007) Sulfonylurea-responsive diabetes in childhood. J Pediatr 150: 553.555
[19]  Aguilar-Bryan L, Bryan J (2008) Neonatal diabetes mellitus. Endocr Rev 29: 265.291
[20]  Murphy R, Ellard S, Hattersley AT (2008) Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab 4: 200.213
[21]  Yorifuji T, Nagashima K, Kurokawa K, Kawai M, Oishi M (2005) The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus. J Clin Endocrinol Metab 90: 3174.3178
[22]  D’Amato E, Tammaro P, Craig TJ, Tosi A, Giorgetti R (2008) Variable phenotypic spectrum of diabetes mellitus in a family carrying a novel KCNJ11 gene mutation. Diabet Med 25: 651.656
[23]  Riveline JP, Rousseau E, Reznik Y, Fetita S, Philippe J (2012) Clinical and Metabolic Features of Adult-Onset Diabetes Caused by ABCC8 Mutations. Diabetes Care 35: 248.251
[24]  Boesgaard TW, Pruhova S, Andersson EA, Cinek O, Obermannova B (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.
[25]  Meur G, Simon A, Harun N, Virally M, Dechaume A (2010) Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention. Diabetes 59: 653.661
[26]  Molven A, Ringdal M, Nordbo AM, Raeder H, Stoy J (2008) Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes 57: 1131.1135
[27]  Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A (2008) Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes 57: 1034.1042
[28]  Chevre JC, Hani EH, Boutin P, Vaxillaire M, Blanche H (1998) Mutation screening in 18 Caucasian families suggest the existence of other MODY genes. Diabetologia 41: 1017.1023
[29]  Balkau B (1996) [An epidemiologic survey from a network of French Health Examination Centres, (D.E.S.I.R.): epidemiologic data on the insulin resistance syndrome]. Rev Epidemiol Sante Publique 44: 373.375
[30]  Vaxillaire M, Boccio V, Philippi A, Vigouroux C, Terwilliger J (1995) A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q. Nat Genet 9: 418.423
[31]  Gudbjartsson DF, Thorvaldsson T, Kong A, Gunnarsson G, Ingolfsdottir A (2005) Allegro version 2. Nat Genet 37: 1015.1016


comments powered by Disqus

Contact Us


微信:OALib Journal