A rare splice site mutation (IVS5; -1G>A) of the GCK gene

Dinara IVANOSHCHUK, Elena SHAKHTSHNEIDER, Alla OVSYANNIKOVA, Svetlana MIKHAILOVA, Oksana RYMAR, Viktoriya OBLAUKHOVA OBLAUKHOVA, Andrey YURCHENKO, Mikhail VOEVODA

Abstract


Maturity onset diabetes of the young (MODY) is a hereditary form of diabetes with an autosomal dominant type of inheritance, onset at a young age, and a primary defect in pancreatic β-cells function. The article presents a variant of maturity onset diabetes of the young type 2, caused by a rare mutation in the GCK gene encoding glucokinase/hexokinase 4. Identified substitution c.580-1G>A [IVS5 (-1G>A)] is located in an acceptor splice site of intron 5 of GCK. A heterozygous mutation in the GCK gene was found by next-generation sequencing. IVS5 (-1G>A) of GCK cosegregates with a pathological phenotype in the examined family members. The GCK gene encodes glucokinase (hexokinase 4), which catalyzes the first step in a large number of glucose metabolic pathways such as glycolysis. Mutations in the GCK gene are the cause of MODY2. The disease is characterized by an insignificant increase in the fasting glucose level, well-controlled disease without medication, and low prevalence of micro- and macrovascular complications of diabetes. When nonclassical diabetes mellitus is being diagnosed in young people, genetic testing is needed to verify the diagnosis.

References


Abramowicz A, Gos M (2018) Splicing mutations in human genetic disorders: examples, detection, and confirmation. Journal Of Applied Genetics 59: 253–268. doi: 10.1007/s13353-018-0444-7

Anık A, Çatlı G, Abacı A, Böber E (2015) Maturity-onset diabetes of the young (MODY): an update. Journal of Pediatric Endocrinology and Metabolism 28: 251-263. doi: 10.1515/jpem-2014-0384

Auton A, Brooks LD, Durbin RM, et al (2015) 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 526: 68-74. doi: 10.1038/nature15393

Bonnefond A, Philippe J, Durand E, et al (201) Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS One 7:e37423. doi: 10.1371/journal.pone.0037423

Caetano LA, Jorge AAL, Malaquias AC, et al (2012) Incidental mild hyperglycemia in children: two MODY 2 families identified in Brazilian subjects. Arquivos brasileiros de endocrinologia e metabologia 56: 519-524. dx.doi.org/10.1590/S0004-27302012000800010

Chakera AJ, Carleton VL, Ellard S et al (2012) Antenatal diagnosis of fetal genotype determines if maternal hyperglycemia due to a glucokinase mutation requires treatment. Diabetes Care 35: 1832-1834. doi: 10.2337/dc12-0151

Chakera AJ, Spyer G, Vincent N, et al (2014) The 0.1% of the population with glucokinase monogenic diabetes can be recognized by clinical characteristics in pregnancy: the Atlantic Diabetes in Pregnancy cohort. Diabetes Care 37: 1230–1236. doi: 10.2337/dc13-2248

Chakera AJ, Steele AM, Gloyn AL et al (2015) Recognition and management of individuals with hyperglycemia because of heterozygous glucokinase mutations. Diabetes Care 38: 1383–1392. doi: 10.2337/dc14-2769

Edghill EL, Minton JA, Groves CJ, et al (2010) Sequencing of candidate genes selected by beta cell experts in monogenic diabetes of unknown aetiology. Journal of Pancreas 11: 14-17. http://dx.doi.org/10.6092/1590-8577/3864

Esmaeilzadeh H, Bordbar MR, Dastsooz H, Silawi M, Fard MAF, Adib A, Kafashan A, Tabatabaei Z, Sadeghipour F, Faghihi MA (2018) A novel splice site mutation in WAS gene in patient with Wiskott-Aldrich syndrome and chronic colitis: a case report. BMC Medical Genetics 19:123. https://doi.org/10.1186/s12881-018-0647-0

Fajans SS, Bell GI, Polonsky KS (2001) Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. The New England Journal of Medicine 345: 971-980. doi: 10.1056/NEJMra002168

Igudin EL, Spirin PV, Prassolov VS, et al (2014) Functional Characterization of Two Novel Splicing Mutations of Glucokinase Gene Associated with Maturity-Onset Diabetes of the Young Type 2 (MODY2). Molecular Biology 48: 248-253. doi: 10.1134/S0026893314020071

Inoue M, Sakuraba Y, Motegi H, et al (2004) A series of maturity onset diabetes of the young, type 2 (MODY2) mouse models generated by a large-scale ENU mutagenesis program. Human Molecular Genetics 13: 1147-1157. doi: 10.1093/hmg/ddh133

Iynedjian PB (2009) Molecular physiology of mammalian glucokinase. Cellular and Molecular Life Sciences 66: 27-42. doi: 10.1007/s00018-008-8322-9

Jang MA, Kim YE, Kim SK, Lee MK, Kim JW, Ki CS (2016) Identification and characterization of NF1 splicing mutations in Korean patients with neurofibromatosis type 1. Journal Human Genetics 61:705–709. DOI: 10.1038/jhg.2016.33

Karczewski KJ, Weisburd B, Thomas B, et al (2017) The ExAC browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Research 45: 840‐845. https://doi.org/10.1093/nar/gkw971

Lachance CH (2016) Practical Aspects of Monogenic Diabetes: A Clinical Point of View. Canadian Journal of Diabetes 40: 368-375. doi: 10.1016/j.jcjd.2015.11.004

Landrum MJ, Lee JM, Riley GR, et al (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Research 42: 980–985. doi:10.1093/nar/gkt1113

Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25: 1754-1760. doi: 10.1093/bioinformatics/btp324

Lorini R, Klersy C, D'Annunzio G, et al (2009) Maturity-onset diabetes of the young in children with incidental hyperglycemia : amulticenter Italian study of 172 families. Diabetes Care 32: 1864-1866. doi: 10.2337/dc08-2018

Ma SL, Vega-Warner V, Gillies C, Sampson MG, Kher V, Sethi SK, Otto EA (2015) Whole exome sequencing reveals novel PHEX splice site mutations in patients with Hypophosphatemic rickets. PLoS One 10:e0130729 https://doi.org/10.1371/journal.pone.0130729

Matschinsky F, Liang Y, Kesavan P, et al (1993) Glucokinase as pancreatic cell glucose sensor and diabetes gene. Journal of Clinical Investigation 92: 2092–2098. doi:10.1172/JCI116809

McDonald TJ, Ellard S (2013) Maturity onset diabetes of the young: Identification and diagnosis. Annals of Clinical Biochemistry 50: 403-415. https://doi.org/10.1177/0004563213483458

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al (2010) The genome analysis toolkit: A mapreduce framework for analyzing next-generation dna sequencing data. Genome Research 20: 1297–1303. doi: 10.1101/gr.107524.110

Osbak KK, Colclough K, Saint-Martin C, et al (2009) Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Human Mutation 30: 1512-1526. doi: 10.1002/humu.21110

Ovsyannikova AK, Rymar OD, Shakhtshneider EV, et al (2016) ABCC8‐related maturity‐onset diabetes of the young (MODY12): clinical features and treatment perspective. Diabetes Therapy 7: 591‐600. https://doi.org/10.1007/s13300‐016‐0192‐9

Plengvidhya N, Boonyasrisawat W, Chongjaroen N, et al (2009) Mutations of maturity-onset diabetes of the young (MODY) genes in Thais with early-onset type 2 diabetes mellitus. Clinical Endocrinology (Oxford) 70: 847–853. https://doi.org/10.1111/j.1365-2265.2008.03397.x

Pruhova S, Dusatkova P, Kraml PJ, et al (2013) Chronic Mild Hyperglycemia in GCK-MODY Patients Does Not Increase Carotid Intima-Media Thickness. International Journal of Endocrinology. 2013: 1-5. doi: 10.1155/2013/718254

Sambrook J, Russell DW (2006) Purification of nucleic acids by extraction with phenol:chloroform. Cold Spring Harb Protocols. doi: 10.1101/pdb.prot4455

Shakhtshneider EV, Ivanoshchuk DЕ, Makarenkova КV, Orlov PS, Timoshchenko ОV, Bazhan SS, Nikitin YuP, Voevoda МI (2017) Cascade genetic screening in diagnostics of heterozygous familial hypercholesterolemia:clinical case. Russian Journal Cardiology 6: 178–179 http://dx.doi.org/10.15829/1560-4071-2017-6-178-179

Sherry ST, Ward MH, Kholodov M, et al (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Research 29: 308-311. https://doi.org/10.1093/nar/29.1.308

Shields BM, Hicks S, Shepherd MH, et al (2010) Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 53: 2504-2508. doi: 10.1007/s00125-010-1799-4

Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP, Liebert CB, Chadwick B, Idelson M, Reznik L, Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod FB, Gusella JF (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. American Journal of Human Genetics. 68:598-605. DOI: 10.1086/318810

Spyer G, Macleod KM, Shepherd M et al (2009) Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabetic Medicine 26: 14-18. doi: 10.1111/j.1464-5491.2008.02622.x

Steele AM, Shields BM, Wensley KJ, et al. (2014) Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. Journal of the American Medical Association 311: 279–286. doi:10.1001/jama.2013.283980

Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN (2017) The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Human Genetics 136: 665–677. doi:10.1007/s00439-017-1779-6

Stride A, Vaxillaire A, Tuomi M, et al (2002) The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia 45: 427–435. doi: 10.1007/s00125-001-0770-9

Thanabalasingham G, Owen KR (2011) Diagnosis and management of maturity onset diabetes of the young (MODY). British Medical Journal 343: d6044. doi: 10.1136/bmj.d6044

Toaima D, Näke A, Wendenburg J, et al (2005) Identification of novel GCK and HNF1A/TCF1 mutations and polymorphisms in German families with maturity-onset diabetes of the young (MODY). Human Mutation 5: 503-504. doi:10.1002/humu.9334

Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high‐throughput sequencing data. Nucleic Acids Research 38: e164. doi: 10.1093/nar/gkq603

Wedrychowicz A, Tobor E, Wilk M, et al (2017) Phenotype Heterogeneity in Glucokinase-Maturity-Onset Diabetes of the Young (GCK-MODY) Patients. Journal of Clinical Research in Pediatric Endocrinology 9: 246-252. doi: 10.4274/jcrpe.4461

Xiong HY, Alipanahi B, Lee LJ, et al (2015) The human splicing code reveals new insights into the genetic determinants of disease. Science 347: 1254806. doi:10.1126/science.1254806


Refbacks

  • There are currently no refbacks.