Original research| Volume 16, ISSUE 2, P325-332, April 2022

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Clinical profiling and screening for HNF4α and GCK gene mutations in Kashmiri patients with maturity-onset diabetes of the young (MODY)

Published:February 04, 2022DOI:


      • Maturity onset diabetes of young.
      • Gene mutations as cause of MODY focussed on HNF4α and GCK.
      • Evaluation of Clinical differences, and Pedigree analysis.
      • Screening of HNF4A and GCK gene mutations by RFLP and Sequencing.
      • Limitations of our research.



      Maturity-onset Diabetes of Young (MODY) is a monogenic form of diabetes affecting 1–5% of young (often ≤25 years) diabetic patients exhibiting an autosomal dominant mode of inheritance. Considering the significance of genetic polymorphisms in a variety of diseases, this study aimed to determine the association between HNF4α and GCK gene polymorphisms and the risk of MODY in the Kashmir community, as well as their clinical differences.


      The study was conducted on clinically confirmed MODY patients (n = 50), and age and gender-matched controls (25 T1DM and 25 non-diabetic) recruited from the endocrinology department of the hospital, for evaluating the HNF4α and GCK mutation. Under standard conditions, PCR-mediated amplification was done to evaluate the respective exons. Preliminary mutations were detected using restriction enzymes (BfaI and HhaI), which were then followed by sequencing of representative samples. The diabetic history, clinical and biochemical data were obtained after proper consent.


      Our data revealed no association of HNF4α (exon7) and GCK (exon8) gene mutation with MODY disease susceptibility in the Kashmiri population. On diagnosis, no MODY patient was given immediate insulin; instead, metformin (68%) or sulphonyl-urea (28%) and dietary changes (4%) were recommended. Later in life, 54% of MODY patients develop insulin dependency. The MODY probability was calculated to be 73.88% (±4.56). HbA1c levels were lower [7.48% (±1.64)] than in T1DM [9.17(±2.29%)].


      Young early-onset diabetic patients were able to keep their HbA1c and blood glucose levels stable with a modified diet and metformin/sulphonyl-urea, but they may become insulin-dependent in the future, as seen in our study. As a result, prompt diagnosis and management are essential for avoiding complications. Furthermore, no HNF4α (exon7) or GCK (exon 8) mutations were found in MODY patients or T1DM/healthy non-diabetic controls.


      MODY (Maturity-onset diabetes of the young), HNF4α (hepatocyte nuclear factor 4 alpha), HNF1α (hepatocyte nuclear factor alpha 1), GCK (Glucokinase), GDM (Gestational diabetes mellitus), PCR (polymerase chain reaction), RFLP (Restriction fragment length polymorphism), T1D (Type1 diabetes)


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        • Gloyn Anna L.
        • Ellard Sian
        • Shepherd Maggie
        • Howell Rodney T.
        • Parry Elizabeth M.
        • Jefferson Andrew
        • Levy Elaine R.
        • Hattersley Andrew T.
        Maturity-onset diabetes of the young caused by a balanced translocation where the 20q12 break point results in disruption upstream of the coding region of hepatocyte nuclear factor-4A gene.
        Diabetes. 2002; 51: 2329-2333
        • Owen K.
        • Hattersley A.
        Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization.
        Best Pract. Res. Clin. Endocrinol. Metab. 2001; 15: 309-323
        • Stride A.
        • Hattersley A.T.
        Different genes, different diabetes: lessons from maturity onset diabetes of the young.
        Ann. Med. 2002; 34: 207-216
        • Firdous P.
        • Nissar K.
        • Ali S.
        • Ganai B.A.
        • Shabir U.
        • Hassan T.
        • Masoodi S.R.
        Genetic testing of maturity-onset diabetes of the young current status and future perspectives.
        Front. Endocrinol. (Lausanne). 2018; 9: 253
        • Skoczek D.
        • Dulak J.
        • Kachamakova-Trojanowska N.
        Maturity onset diabetes of the young—new approaches for disease modelling.
        Int. J. Mol. Sci. 2021; 22: 7553
        • Sladek F.M.
        • Zhong W.M.
        • Lai E.
        • Darnell Jr., J.E.
        Liver enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily.
        Genes Dev. 1990; 4: 2353-2365
        • Jiang G.
        • Sladek F.M.
        The DNA binding domain of hepatocyte nuclear factor 4 mediates cooperative, specific binding to DNA and heterodimerization with the retinoid X receptor alpha.
        J. Biol. Chem. 1997; 272: 1218-1225
        • Mietus-Snyder M.
        • Sladek F.M.
        • Ginsburg G.S.
        • Guo C.F.
        • Ladias J.A.
        • Darnell Jr., J.E.
        • Karathanasis S.K.
        Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells.
        Mol. Cell. Biol. 1992; 12: 1708-1718
        • Ladias J.A.
        • Hadzopoulou-Cladaras M.
        • Kardassis D.
        • et al.
        Transcriptional regulation of human apolipoprotein genes ApoB, ApoCIII, and ApoAII by members of the steroid hormone receptor superfamily HNF-4, ARP-1, EAR-2, and EAR-3.
        J. Biol. Chem. 1992; 267: 15849-15860
        • Stoffel M.
        • Duncan S.A.
        The maturity-onset diabetes of the young (MODY1) transcription factor HNF4a regulates expression of genes required for glucose transport and metabolism.
        Proc. Natl. Acad. U.S.A. 1997; 94: 13209-13214
        • Duncan S.A.
        • Nagy A.
        • Chan W.
        Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of Hnf-4(-/-) embryos.
        Development (Cambridge, UK). 1997; 124: 279-287
        • Wang H.
        • Maechler P.
        • Antinozzi P.A.
        • Hagenfeldt K.A.
        • Wollheim
        • CB
        Hepatocyte nuclear factor 4α regulates the expression of pancreatic β-cell genes implicated in glucose metabolism and nutrient-induced insulin secretion.
        J. Biol. Chem. 2000; 275: 35953-35959
        • Yamagata K.
        • Furuta H.
        • Oda N.
        • Kaisaki P.
        • Menzel S.
        • Cox N.J.
        • Fajans S.S.
        • Signorini S.
        • Stoffel M.
        • Bell G.I.
        Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1).
        Nature (London). 1996; 384: 458-460
        • Al-Kandari H.
        • Al-Abdulrazzaq D.
        • Davidsson L.
        • et al.
        Identification of Maturity-Onset-Diabetes of the Young (MODY) mutations in a country where diabetes is endemic.
        Sci. Rep. 2021; 1116060
        • Pingul M.M.
        • Hughes N.
        • Wu A.
        • Stanley C.A.
        • Gruppuso P.A.
        Hepatocyte nuclear factor‑ 4α gene mutation associated with familial neonatal hyperinsulinism and maturity onset diabetes of the young.
        J. Pediatr. 2011; 158: 852-854
        • MCdonald T.J.
        • Ellard S.
        Maturity onset diabetes if the young; identification and diagnosis.
        Clin. Biochem. Ann. 2013; 50: 403-415
        • Flanagan S.E.
        • Kapoor R.R.
        • Mali G.
        Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF1A gene mutation.
        Eur. J. Endocrinol. 2010; 16: 987-992
        • Schuit F.C.
        • Huypens P.
        • Heimberg H.
        • Pipeleers D.G.
        Glucose sensing in pancreatic beta-cells: a model for the study of other glucose-regulated cells in gut, pancreas, and hypothalamus.
        Diabetes. 2001; 50: 1-11
        • Matschinsky F.M.
        • Liang Y.
        • Kesavan P.
        • Wang L.
        • Froguel P.
        • Velho G.
        • Cohen D.
        • Permutt M.A.
        • Tanizawa Y.
        • Jetton T.L.
        • Niswender K.
        • Magnuson M.A.
        Glucokinase as pancreatic beta cell glucose sensor and diabetes gene.
        J. Clin. Invest. 1993; 92: 2092-2098
        • Fajan S.S.
        • Bell G.I.
        • Polonsky K.S.
        Molecular mechanisms and clinical patho-physiology of maturity-onset diabetes of the young.
        N. Engl. J. Med. 2001; 345: 971-980
        • Chakera A.J.
        • Spyer G.
        • Vincent N.
        • et al.
        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. 2014; 37: 1230-1236
        • Osbak K.K.
        • Colclough K.
        • Saint-Martin C.
        • Beer N.L.
        • Bellanné-Chan- telot 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: 1512-1526
        • Steele A.M.
        • Shields B.M.
        • Wensley K.J.
        • et al.
        Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia.
        JAMA. 2014; 311: 279-286
        • Suguna Sajja
        • Nandal D.H.
        • Kamble Suresh
        • Bharatha Ambadasu
        • Kunkulol Rahul
        Genomic DNA isolation from human whole blood samples by non enzymatic salting out method.
        Int. J. Pharm. Pharm. Sci. 2014; 6: 198-199
        • Sang Y.
        • Xu Z.
        • Liu M.
        • Yan J.
        • Wu Y.
        • Zhu C.
        • Ni G.
        Mutational analysis of ABCC8, KCNJ11, GLUD1, HNF4A and GCK genes in 30 Chinese patients with congenital hyperinsulinism.
        Endocr. J. 2014; 61: 901-910
        • Khalil R.
        • Al-Sheyab F.
        • Khamaiseh E.
        • Halaweh M.A.
        • Abder-Rahman H.A.
        Screening of mutations in the GCK gene in Jordanian maturity-onset diabetes of the young type 2 (MODY2) patients.
        Genet. Med. Res. 2009; 8: 500-506
        • Shields B.M.
        • McDonald T.J.
        • Ellard S.
        • Campbell M.J.
        • Hyde C.
        • Hattersley A.T.
        The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes.
        Diabetologia. 2012; 55: 1265-1272
        • Nkonge K.M.
        • Nkonge D.K.
        • Nkonge T.N.
        The epidemiology, molecular pathogenesis, diagnosis, and treatment of maturity-onset diabetes of the young (MODY).
        Clin. Diabetes Endocrinol. 2020; 6: 20
        • Pearson E.R.
        • Velho G.
        • Clark P.
        • Stride A.
        • Shepherd M.
        • Frayling T.M.
        • et al.
        Beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1alpha and glucokinase mutations.
        Diabetes. 2001; 50: 101-107
        • Velho G.
        • Froguel P.
        • Gloyn A.
        • Hattersley A.T.
        Glucokinase and the regulation of blood glucose.
        in: Matschinsky F. Magnuson M.A. Glucokinase and Glycemic Disease. From Basics to Novel Therapeutics. Karger, Basel2004: 42-64
        • Gaál Z.
        • Sz ̋ucs Z.
        • Kántor I.
        • Luczay A.
        • Tóth-Heyn P.
        • Benn O.
        • Felszeghy E.
        • Karádi Z.
        • Madar L.
        • Balogh I.
        A comprehensive analysis of Hungarian MODY patients—part II: Glucokinase MODY is the most prevalent subtype responsible for about 70% of confirmed cases.
        Life. 2021; 11: 771
        • Stoffel M.
        • Patel P.
        • Lo Y.M.-D.
        • et al.
        Characterisation of a missense glucokinase mutation in maturity-onset diabetes of the young (MODY) and mutation screening in late-onset diabetes.
        Nat. Genet. 1992; 2: 153-156
        • Page R.C.L.
        • Hattersley A.T.
        • Levy J.C.
        • et al.
        Clinical characteristics of subjects with a missense mutation in glucokinase.
        Diabet. Med. 1995; 12: 209-217
        • Saker P.J.
        • Hattersley A.T.
        • Barrow B.
        • Hammersley M.S.
        • McLellan J.-A.
        • Lo Y.-M.D.
        • Olds R.J.
        • Gillmer M.D.
        • Holman R.R.
        • Turner R.C.
        High prevalence of amissense mutation of the glucokinase gene in gestational diabetic patients dueto a founder-effect in a local population.
        Diabetologia. 1996; 39: 1325-1328
        • Laver Thomas W.
        • Colclough Kevin
        • Shepherd Maggie
        • Patel Kashyap
        • Houghton Jayne A.L.
        • Dusatkova Petra
        • Pruhova Stepanka
        • Morris Andrew D.
        • Palmer Colin N.
        • McCarthy Mark I.
        • Ellard Sian
        • Hattersley Andrew T.
        • Weedon Michael N.
        The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes.
        Diabetes. 2016; 65: 3212-3217
        • Furuta H.
        • Iwasaki N.
        • Oda N.
        • et al.
        Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY.
        Diabetes. 1997; 46: 1652-1657
        • Delvecchio M.
        • Ludovico O.
        • Menzaghi C.
        • et al.
        Low prevalence of HNF1A mutations after molecular screening of multiple MODY genes in 58 Italian families recruited in the pediatric or adult diabetes clinic from a single Italian hospital.
        Diabetes Care. 2014; 37 (6): e258-e260
        • Ludovico O.
        • Carella M.
        • Bisceglia L.
        • et al.
        Identification and clinical characterization of adult patients with multigenerational diabetes mellitus.
        PLoS One. 2015; 10e0135855
        • Kyithar M.P.
        • Bacon S.
        • Pannu K.K.
        • Rizvi S.R.
        • Colclough K.
        • Ellard S.
        • Byrne M.M.
        Identification of HNF1A-MODY and HNF4A-MODY in Irish families: phenotypic characteristics and therapeutic implications.
        Diabetes Metab. 2011; 37: 512-519