Molecular genetic study in a cohort of Iranian families suspected to maturity-onset diabetes of the young, reveals a recurrent mutation and a high-risk variant in the CEL gene


1 Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran

2 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

3 Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Science, Isfahan, Iran

4 Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

5 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences; Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran


Background: Diabetes mellitus (DM) is a group of metabolic disorders in the body, accompanied with increasing blood sugar levels. Diabetes is classified into three groups: Type 1 DM (T1DM), Type 2 DM (T2DM), and monogenic diabetes. Maturity-onset diabetes of the young (MODY) is a monogenic diabetes that is frequently mistaken for T1D or T2D. The aim of this study was to diagnose MODY and its subtype frequency in a diabetic population in Iran. Materials and Methods: In this study among ten diabetic families that were highly suspected to MODY by nongenetic biomarkers and without any pathogenic mutation in GCK and HNF1A genes, two patients from two unrelated families were examined via whole-exome sequencing (WES) in order to detect the causative gene of diabetes. Co-segregation analysis of the identified variant was performed using Sanger sequencing. Results: In this study, no pathogenic variant was found in GCK and HNF1A genes (MODY2 and MODY3), while these two types of MODY were introduced as the most frequent in other studies. By using WES, a pathogenic variant (p.I488T) was found in one of the patients in CEL gene causing MODY8 that its frequency is very rare in other studied populations. A high-risk variant associated with diabetes was found in another patient. Conclusion: WES was applied in this study to reveal the cause of MODY in 1 family. This pathogenic mutation was previously reported as a disease causing mutation.


American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014;37 Suppl 1:S81-90.  Back to cited text no. 1
Bansal V, Gassenhuber J, Phillips T, Oliveira G, Harbaugh R, Villarasa N, et al. Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals. BMC Med 2017;15:213.  Back to cited text no. 2
Katsarou A, Gudbjörnsdottir S, Rawshani A, Dabelea D, Bonifacio E, Anderson BJ, et al. Type 1 diabetes mellitus. Nat Rev Dis Primers 2017;3:17016.  Back to cited text no. 3
DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers 2015;1:15019.  Back to cited text no. 4
Greeley SA, Naylor RN, Philipson LH, Bell GI. Neonatal diabetes: An expanding list of genes allows for improved diagnosis and treatment. Curr Diab Rep 2011;11:519-32.  Back to cited text no. 5
Delvecchio M, Mozzillo E, Salzano G, Iafusco D, Frontino G, Patera PI, et al. Monogenic Diabetes Accounts for 6.3% of Cases Referred to 15 Italian Pediatric Diabetes Centers During 2007 to 2012. J Clin Endocrinol Metab 2017;102:1826-34.  Back to cited text no. 6
Anık A, Çatlı G, Abacı A, Böber E. Maturity-onset diabetes of the young (MODY): An update. J Pediatr Endocrinol Metab 2015;28:251-63.  Back to cited text no. 7
Tattersall R. Maturity-onset diabetes of the young: A clinical history. Diabet Med 1998;15:11-4.  Back to cited text no. 8
Tattersall RB, Fajans SS. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes 1975;24:44-53.  Back to cited text no. 9
Tattersall RB. Mild familial diabetes with dominant inheritance. Q J Med 1974;43:339-57.  Back to cited text no. 10
Siddiqui K, Musambil M, Nazir N. Maturity onset diabetes of the young (MODY)--history, first case reports and recent advances. Gene 2015;555:66-71.  Back to cited text no. 11
Radha V, Mohan V. Genetic basis of monogenic diabetes. Curr Sci 2017;113:1277.  Back to cited text no. 12
Torsvik J, Johansson S, Johansen A, Ek J, Minton J, Raeder H, et al. Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes. Hum Genet 2010;127:55-64.  Back to cited text no. 13
Kolar MJ, Kamat SS, Parsons WH, Homan EA, Maher T, Peroni OD, et al. Branched Fatty Acid Esters of Hydroxy Fatty Acids Are Preferred Substrates of the MODY8 Protein Carboxyl Ester Lipase. Biochemistry 2016;55:4636-41.  Back to cited text no. 14
Aho HJ, Sternby B, Kallajoki M, Nevalainen TJ. Carboxyl ester lipase in human tissues and in acute pancreatitis. Int J Pancreatol 1989;5:123-34.  Back to cited text no. 15
Torsvik J, Johansson BB, Dalva M, Marie M, Fjeld K, Johansson S, et al. Endocytosis of secreted carboxyl ester lipase in a syndrome of diabetes and pancreatic exocrine dysfunction. J Biol Chem 2014;289:29097-111.  Back to cited text no. 16
Kleinberger JW, Pollin TI. Undiagnosed MODY: Time for Action. Curr Diab Rep 2015;15:110.  Back to cited text no. 17
Sanyal D, Majumder A, Chaudhuri SR, Chatterjee S. Thyroid profile and autoantibodies in Type 1 diabetes subjects: A perspective from Eastern India. Indian J Endocrinol Metabolism 2017;21:45.  Back to cited text no. 18
McDonald TJ, Colclough K, Brown R, Shields B, Shepherd M, Bingley P, et al. Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes. Diabet Med 2011;28:1028-33.  Back to cited text no. 19
Amed S, Oram R. Maturity-Onset Diabetes of the Young (MODY): Making the Right Diagnosis to Optimize Treatment. Can J Diabetes 2016;40:449-54.  Back to cited text no. 20
Irgens HU, Molnes J, Johansson BB, Ringdal M, Skrivarhaug T, Undlien DE, et al. Prevalence of monogenic diabetes in the population-based Norwegian Childhood Diabetes Registry. Diabetologia 2013;56:1512-9.  Back to cited text no. 21
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-24.  Back to cited text no. 22
Pires DE, Ascher DB, Blundell TL. mCSM: Predicting the effects of mutations in proteins using graph-based signatures. Bioinformatics 2014;30:335-42.  Back to cited text no. 23
Johansen CT, Dubé JB, Loyzer MN, MacDonald A, Carter DE, McIntyre AD, et al. LipidSeq: A next-generation clinical resequencing panel for monogenic dyslipidemias. J Lipid Res 2014;55:765-72.  Back to cited text no. 24
Exposito MR, Sanchez IP, Moreno P, Moreno MA, editors. Debut Diabetes Characteristics. 19th European Congress of Endocrinology. Portugal: BioScientifica; 2017.  Back to cited text no. 25
Prudente S, Jungtrakoon P, Marucci A, Ludovico O, Buranasupkajorn P, Mazza T, et al. Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus. Am J Hum Genet 2015;97:177-85.  Back to cited text no. 26
Kim SH. Maturity-onset diabetes of the young: What do clinicians need to know? Diabetes Metab J 2015;39:468-77.  Back to cited text no. 27
Johansson BB, Torsvik J, Bjørkhaug L, Vesterhus M, Ragvin A, Tjora E, et al. Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl ester lipase gene-maturity onset diabetes of the young (CEL-MODY): A protein misfolding disease. J Biol Chem 2011;286:34593-605.  Back to cited text no. 28
Lombardo D. Bile salt-dependent lipase: Its pathophysiological implications. Biochim Biophys Acta 2001;1533:1-28.  Back to cited text no. 29
Nilsson J, Bläckberg L, Carlsson P, Enerbäck S, Hernell O, Bjursell G. cDNA cloning of human-milk bile-salt-stimulated lipase and evidence for its identity to pancreatic carboxylic ester hydrolase. Eur J Biochem 1990;192:543-50.  Back to cited text no. 30
Lombardo D, Guy O. Studies on the substrate specificity of a carboxyl ester hydrolase from human pancreatic juice. II. Action on cholesterol esters and lipid-soluble vitamin esters. Biochim Biophys Acta 1980;611:147-55.  Back to cited text no. 31
Roudani S, Miralles F, Margotat A, Escribano MJ, Lombardo D. Bile salt-dependent lipase transcripts in human fetal tissues. Biochim Biophys Acta 1995;1264:141-50.  Back to cited text no. 32
Lombardo D, Silvy F, Crenon I, Martinez E, Collignon A, Beraud E, et al. Pancreatic adenocarcinoma, chronic pancreatitis, and MODY-8 diabetes: Is bile salt-dependent lipase (or carboxyl ester lipase) at the crossroads of pancreatic pathologies? Oncotarget 2018;9:12513-33.  Back to cited text no. 33
Johansson BB, Fjeld K, El Jellas K, Gravdal A, Dalva M, Tjora E, et al. The role of the carboxyl ester lipase (CEL) gene in pancreatic disease. Pancreatology 2018;18:12-9.  Back to cited text no. 34
Xiao X, Jones G, Sevilla WA, Stolz DB, Magee KE, Haughney M, et al. A carboxyl ester lipase (CEL) mutant causes chronic pancreatitis by forming intracellular aggregates that activate apoptosis. J Biol Chem 2017;292:7744.  Back to cited text no. 35
Vesterhus M, Raeder H, Kurpad AJ, Kawamori D, Molven A, Kulkarni RN, et al. Pancreatic function in carboxyl-ester lipase knockout mice. Pancreatology 2010;10:467-76.  Back to cited text no. 36
Bläckberg L, Lombardo D, Hernell O, Guy O, Olivecrona T. Bile salt-stimulated lipase in human milk and carboxyl ester hydrolase in pancreatic juice: Are they identical enzymes? FEBS Lett 1981;136:284-8.  Back to cited text no. 37
Ming-Qiang Z, Yang-Li D, Ke H, Wei W, Jun-Fen F, Chao-Chun Z, et al. Maturity onset diabetes of the young (MODY) in Chinese children: Genes and clinical phenotypes. J Pediatr Endocrinol Metab 2019;32:759-65.  Back to cited text no. 38
Moghbeli M, Naghibzadeh B, Ghahraman M, Fatemi S, Taghavi M, Vakili R, et al. Mutations in HNF1A Gene are not a Common Cause of Familial Young-Onset Diabetes in Iran. Indian J Clin Biochem 2018;33:91-5.  Back to cited text no. 39
Mohammadi A, Eskandari A, Sarmadi A, Rahimi M, Iraj B, Hashemipour M, et al. Genetic Study of Hepatocyte Nuclear Factor 1 Alpha Variants in Development of Early-Onset Diabetes Type 2 and Maturity-Onset Diabetes of the Young 3 in Iran. Adv Biomed Res 2019;8:55.  Back to cited text no. 40
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Zhang M, Zhou JJ, Cui W, Li Y, Yang P, Chen X, et al. Molecular and phenotypic characteristics of maturity-onset diabetes of the young compared with early onset type 2 diabetes in China. J Diabetes 2015;7:858-63.  Back to cited text no. 41
George DC, Chakraborty C, Haneef SA, Nagasundaram N, Chen L, Zhu H. Evolution- and structure-based computational strategy reveals the impact of deleterious missense mutations on MODY 2 (maturity-onset diabetes of the young, type 2). Theranostics 2014;4:366-85.  Back to cited text no. 42
Wakil SM, Muiya NP, Tahir AI, Al-Najai M, Baz B, Andres E, et al. A new susceptibility locus for myocardial infarction, hypertension, type 2 diabetes mellitus, and dyslipidemia on chromosome 12q24. Dis Markers 2014;2014:291419.  Back to cited text no. 43
Chapla A, Mruthyunjaya MD, Asha HS, Varghese D, Varshney M, Vasan SK, et al. Maturity onset diabetes of the young in India-a distinctive mutation pattern identified through targeted next-generation sequencing. Clin Endocrinol (Oxf) 2015;82:533-42.  Back to cited text no. 44