Diabetes Metab J > Volume 39(6); 2015 > Article
Kim: Maturity-Onset Diabetes of the Young: What Do Clinicians Need to Know?

Abstract

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes that is characterized by an early onset, autosomal dominant mode of inheritance and a primary defect in pancreatic β-cell function. MODY represents less than 2% of all diabetes cases and is commonly misdiagnosed as type 1 or type 2 diabetes mellitus. At least 13 MODY subtypes with distinct genetic etiologies have been identified to date. A correct genetic diagnosis is important as it often leads to personalized treatment for those with diabetes and enables predictive genetic testing for their asymptomatic relatives. Next-generation sequencing may provide an efficient method for screening mutations in this form of diabetes as well as identifying new MODY genes. In this review, I discuss a current update on MODY in the literatures and cover the studies that have been performed in Korea.

INTRODUCTION

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes that is characterized by an early onset, autosomal dominant mode of inheritance and a primary defect in pancreatic β-cell function. In 1974, it was first described by Tattersall [1] with a mild form of diabetes in three families who had a dominant mode of inheritance. In the 1990s, advances in molecular genetics and the availability of large pedigrees aided in the identification of genes that are responsible for this form of diabetes. MODY has been well characterized in European and North American populations. MODY is a common form of monogenic diabetes and it may account for 1% to 2% of all diabetes cases in Europe [2]. Although MODY has been identified in Asian populations, the prevalence is not known. In this review, I summarize a current update of MODY and cover the studies that have been conducted in Korean MODY subjects.

CLASSIFICATION OF MODY AND PHENOTYPIC CHARACTERISTICS

Genetic heterogeneity of MODY

Even though MODY is well known as a monogenic disorder, it is not a single entity but represents genetic, metabolic, and clinical heterogeneity [3]. Genes that are known to cause MODY are: hepatocyte nuclear factor 4 α (HNF4A; MODY1), glucokinase (GCK; MODY2), HNF1A (MODY3), pancreatic and duodenal homeobox 1 (PDX1; MODY4), transcription factor 2 (TCF2) or HNF1B (MODY5), neurogenic differentiation 1 (NEUROD1; MODY6), Kruppel-like factor 11 (KLF11; MODY 7), carboxyl ester lipase (CEL; MODY8), paired-box-containing gene 4 (PAX4; MODY9), insulin (INS; MODY10), B-lymphocyte kinase (BLK; MODY11), adenosine triphosphate (ATP)-binding cassette, sub-family C (CFTR/MRP), member 8 (ABCC8; MODY12), and potassium channel, inwardly rectifying subfamily J, member 11 (KCNJ 11; MODY13). The 13 MODY genes thus far identified do not account for all cases of MODY; thus, additional genes responsible for MODY exist and remain to be identified.
Mutations in the GCK, HNF1A, HNF4A, and HNF1B genes are the most common causes of MODY, and they respectively account for 32%, 52%, 10%, and 6% of cases in the UK [4]. However, the disease-causing mutations in Asian and Caucasian MODY patients are different. In Korea, only 10% of 40 MODY or early onset type 2 diabetes mellitus (T2DM) patients had known MODY gene defects (HNF1A 5%, GCK 2.5%, and HNF1B 2.5%) among MODY 1-6 genes [5,6]. Only 10% to 20% of MODY cases are caused by Known MODY genes in Japan and China [7,8]. So, more MODY genes should be discovered in Asian countries. Genes causing MODY and their clinical and molecular characteristics are summarized in Table 1.

MODY subtypes and their clinical characteristics

GCK-MODY (MODY2)

GCK is a glycolytic enzyme that catalyzes the conversion of glucose to glucose-6-phosphate and is referred to as the β-cell glucose sensor because it controls glucose-mediated insulin release. Heterozygous inactivating mutations in GCK cause GCK-MODY, also known as MODY2, which was first recognized in 1992 [9]. A total of 620 mutations in 1,441 families have been identified so far to cause hypoglycemia and hyperglycemia [10]. GCK mutations have been reported throughout the world. In one study of Japanese patients with pediatric-onset MODY-type diabetes, GCK-MODY was reportedly the most common form (approximately 48%) [11]. This proportion was similar to a report in European population [12]. However, only a small proportion (<5%) of MODY cases were caused by GCK-MODY in Korea and China [6,8].
The clinical disease manifests as mild fasting hyperglycemia (5.5 to 8.0 mmol/L, glycosylated hemoglobin range 5.8% to 7.6%) from birth that demonstrates slight deterioration with age. Patients are usually asymptomatic, so many are first discovered during routine screening such as during pregnancy. Severe hyperglycemia and microvascular complications are rare in GCK diabetes [13]. Clinical features of the Japanese patients with GCK-MODY were similar to those that had been previously reported for Caucasians, although 25% of patients demonstrated signs of insulin resistance [14].
Patients with GCK-MODY do not require treatment outside pregnancy because glucose-lowering therapy is ineffective and there is a lack of long-term complications [15]. In pregnancy, insulin may be required to prevent fetal overgrowth. The fetal growth in pregnancy is dependent on whether the mutation is inherited [16]. Management of pregnant women with GCK-MODY is based on fetal growth scans which are surrogates for fetal genotype.

HNF1A-MODY (MODY3)

HNF1A is a homeodomain-containing transcription factor, which is expressed in the liver, kidney, intestine, and pancreatic β-cells. Hnf1a-knockout mice developed diabetes because of impaired glucose-induced insulin secretion [17]. Mutations in HNF1A are the most common cause of MODY in Europe, North America, and Asia [18]. In Asia, 5% to 20% of MODY cases are caused by HNF1A mutations. A total of 414 different HNF1A mutations in 1,247 families have been discovered [19]. Although mutations are located throughout the minimal promoter, exons and flanking intronic regions, they are more often detected in exons 2 and 4. A novel missense mutation (R263L) of HNF1A was found in a Korean MODY family and reportedly caused diabetes through defective glucose sensing and insulin secretion [20].
Heterozygous HNF1A mutations result in progressive β-cell dysfunction that leads to diabetes in early adult life. These mutations demonstrate high penetrance; 63% of carriers develop diabetes by 25 years of age, and almost all carriers develop diabetes by the age of 55 [21]. Carriers develop glycosuria even before diabetes because of decreased renal glucose reabsorption [22]. Because hyperglycemia may be severe and worsens over time, the risks of microvascular and macrovascular complications are similar to type 1 diabetes mellitus (T1DM) and T2DM [23]. Therefore, tight glycemic control and close monitoring for diabetic complications are required in these patients.
Patients with HNF1A-MODY are sensitive to sulfonylurea therapy, which is recommended as first line treatment. An observational study suggests that patients with HNF1A-MODY can be switched safely from insulin to a sulfonylurea [24]. In a series of 43 diabetic patients, 34 switched from insulin to a sulfonylurea after HNF1A-MODY diagnosis, and 24 remained on sulfonylurea for 39 months with excellent glycemic control [25]. Good control may be maintained for many years, although most patients eventually progress to insulin treatment.

HNF4A-MODY (MODY1)

This was the first MODY to be described. HNF4A is a transcription factor that is expressed in the liver, intestine, kidney, and pancreatic islets. It is involved in the regulation of genes that are required for glucose transport and metabolism [26]. HNF4A mutations represent less than 10% of MODY cases in Europe, and more than 103 mutations in 173 families have been identified so far [19]. The clinical profile of heterozygous HNF4A mutations is similar to HNF1A MODY. It is estimated that 10% to 29% of HNF1A-negative patients actually have HNF4A mutations [27]. Patients with HNF4A diabetes are seldom diagnosed before adolescence. Heterozygous HNF4A mutations result in significant fetal macrosomia by increasing insulin secretion in utero and subsequent neonatal hypoglycemia [28]. Glycosuria does not present in HNF4A MODY, and low apolipoproteins (apoA11, apoCIII, and apoB) can be a diagnostic clue [29]. A similar response to sulfonylureas has been observed in patients with HNF4A-MODY [27].

PDX1-MODY (MODY4)

PDX1 (also known as insulin promoter factor 1 [IPF1]) is a homeodomain-containing transcription factor that acts in pancreas development and insulin gene expression [30]. Homozygous mutations can cause permanent neonatal diabetes due to pancreas agenesis [31]. Heterozygous PDX1 mutations lead to β-cell dysfunction and MODY. PDX1-MODY is a very rare cause of MODY and was first described in 1997 [32].

HNF1B-MODY (MODY5)

HNF1B is encoded by the TCF2 gene, which is expressed in the liver, kidney, intestine, stomach, lung, ovary, and pancreatic islets and influences their embryonic development [33]. This form of diabetes is caused by heterozygous mutations in HNFIB, and is characterized by progressive nondiabetic renal dysfunction of variable severity, pancreatic atrophy and genital abnormalities [34,35,36]. It is also called RCAD (renal cysts and diabetes syndrome). More than 65 mutations have been detected to date. Exon or complete gene deletions account for approximately half of cases [37]. A heterozygous P159L HNF1B mutation in a Korean family reportedly has functional consequences on glucose metabolism [38].
Birth weight can be significantly reduced by 900 g due to reduced insulin secretion in utero [35]. Half of carriers develop diabetes. Spontaneous de novo mutations occur relatively frequently; thus, a positive family history should not be required for diagnosis [39]. HNF1B-MODY phenotypes are different from HNF1A-MODY because diabetes develops due to both insulin resistance and defective insulin secretion. Patients with HNF1B-MODY do not respond well to sulfonylureas and usually require early insulin therapy [40].

NEUROD1-MODY (MODY6)

NEUROD1 is a basic-loop-helix transcription factor that is involved in pancreatic and neuronal development. Heterozygous NEUROD1 mutations lead to diabetes as children or adults while mutations in both alleles result in neonatal diabetes with neurological abnormalities and learning disabilities [41,42,43].

KLF11-MODY (MODY7)

KLF11 is a zinc-finger transcription factor that is expressed in pancreatic islet cells. KLF11 binds to and activates the insulin promoter in mouse insulinoma cell lines in a high-glucose condition, which indicates that KLF11 is a glucose-inducible regulator of the insulin gene [44]. Two rare variants of KLF11 gene were identified in three families with early onset T2DM [45].

CEL-MODY (MODY8)

CEL is expressed in mammary glands and pancreatic acinar cells. CEL, also called bile salt-stimulated lipase, is a major component of pancreatic juice and is responsible for the hydrolysis of cholesterol esters as well as a variety of other dietary esters. CEL-MODY was first identified by Raeder et al. [46] in 2 Norwegian kindreds with autosomal dominant diabetes. Heterozygous mutations in the CEL gene result in pancreatic atrophy, fibrosis, and lipomatosis together with exocrine insufficiency and later endocrine dysfunction and diabetes [47].

PAX4-MODY (MODY9)

PAX4 is a transcription factor that is essential for differentiation of insulin-producing β-cells in the mammalian pancreas. PAX4 gene mutations have been identified in Thai probands with MODY who did not have mutations in known MODY genes [48]. It has also been associated with ketosis-prone diabetes [49].

INS-MODY (MODY10)

While INS gene mutations are a common cause of neonatal diabetes, they are also rare causes of diabetes in childhood or adulthood [50]. Heterozygous INS gene mutations decrease proinuslin molecule folding or cause β-cell apoptosis in the endoplasmic reticulum [51]. The treatment is generally insulin, although some patients manage with oral antidiabetic drugs.

BLK-MODY (MODY11)

BLK is a non-receptor tyrosine-kinase of the src family of proto-oncogenes, which acts as a stimulator of insulin synthesis and secretion in pancreatic β-cells via the transcription factors Pdx1 and Nkx6.1 [52]. Kim et al. [53] initially mapped this locus on chromosome 8p23 by a genomewide scan of 21 extended United States families segregating autosomal dominant MODY not caused by known MODY genes. They noted that there was a higher prevalence of obesity in individuals with diabetes that was linked to 8p23 than in diabetic individuals with MODY linked to other loci. Borowiec et al. [52] reported that mutations in BLK caused diabetes in three families.

ABCC8-MODY (MODY12)

The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic β-cell ATP-sensitive potassium (K-ATP) channel. Its activating homo- and heterozygous mutations cause neonatal diabetes, but heterozygous mutations can also cause MODY in patients whose clinical features are similar to those with HNF1A/4A MODY [54]. The correct molecular diagnosis is important, as these patients can be treated with sulfonylureas.

KCNJ11-MODY (MODY13)

The KCNJ11 gene encodes Kir6.2, a part of the K-ATP channel. Its activating homozygous mutations cause neonatal diabetes, but heterozygous mutations have been associated with a large spectrum of diabetes phenotypes in a French family [55]. The age at diagnosis varied from childhood to adulthood (13 to 59 years), and the treatment varied from diet to OAD or insulin. Of the 4 affected individuals, 2 maintained diabetes control with sulfonylurea therapy alone. Heterozygous KCNJ11 mutations were identified in Chinese family with early onset T2DM [56].

MODY STUDIES IN KOREA

Although MODY has been identified in Asian populations, the prevalence of MODY is not known in Korea. In a study of Korean population, only 10% of 40 MODY or early onset T2DM patients had known MODY gene defects (HNF1A 5%, GCK 2.5%, and HNF1B 2.5%) among MODY 1-6 genes [5,6]. This result may be similar to reports from Japan and China [7,8]. The different genetic subtypes could possibly be responsible for Korean patients with MODY. Shim et al. [57] conducted whole-exome sequencing in Korean MODY families, and they could not find any Known MODY mutations but identified variants in protein tyrosine phosphatase, receptor type, D (PTPRD), synaptotagmin-9 (SYT9), and Wolfram syndrome 1 (WFS1). Mutation studies performed in Korean MODY or early onset T2DM patients are summarized in Table 2 [58,59,60,61].

MODY DIAGNOSIS

Although MODY represents 1% to 2% of all diabetes, MODY diagnosis is very important for patients and their families. A correct molecular diagnosis can help identify an optimal treatment strategy. Patients who have been on insulin therapy following T1DM diagnosis can be switched to oral agents (i.e., sulfonylureas) after a diagnosis of HNF1A-MODY or HNF4A-MODY, which will not only improve their quality of life but also often their glycemic control [24]. A molecular diagnosis of MODY can also affect patient prognosis. A patient with mild hyperglycemia in adolescence and a diagnosis of GCK-MODY, HNF1A-MODY, or T1DM will need different treatment and follow-up [13,23]. Finally, family members of affected MODY patients can be screened for their carrier status to predict disease. Genetic testing should be recommended to all family members, while unaffected relatives should receive genetic counseling regarding the benefits and potential consequences of genetic diagnosis.
MODY can be diagnosed by direct sequencing with up to 100% sensitivity [4]. Next generation sequencing strategies have been employed successfully to identify MODY gene mutations using gene targeted and whole-exome sequencing [62,63]. However, molecular genetic testing is expensive and is only available in specialized laboratories. Furthermore, the clinical features of MODY often overlap with both common types of diabetes. In a UK report, more than 80% of patients with MODY are incorrectly diagnosed with T1DM and T2DM at presentation, and patients experienced a delay of 12 years from the time of receiving a diabetes diagnosis to receiving a MODY diagnosis [64].
A targeted selection of individuals for molecular genetic testing is necessary to improve diagnostic yields especially in regions with limited resources. Various algorithms using clinical and laboratory parameters have been proposed to choose individual candidates for molecular diagnosis [65,66] Shields et al. [66] developed a model that discovered that age at diagnosis below 30 years was the most useful discriminator between MODY and T2DM, and a family history of diabetes increased the probability of MODY diagnosis by 23 times in those who had been initially labeled as T1DM. This model determines the probability of MODY in young-onset diabetes (http://www.diabetesgenes.org/content/mody-probability-calcualtor).
The cost and limitations of accessing genetic testing has prompted much efforts to discover nongenetic biomarkers that might identify appropriate candidates for molecular diagnosis. Because patients with HNF1A-MODY have significantly lower levels of high-sensitivity C-reactive protein (hs-CRP) than those with other types of diabetes (T2DM, T1DM, and GCK-MODY), hs-CRP has been used as a marker for differential diagnosis [67,68,69]. A recent study raised the possibility of microRNAs as a biomarker of HNF1A-MODY [70]. Fig. 1 shows a diagnostic algorithm that could be used to identify which young adult with diabetes should be referred for MODY genetic testing.

CONCLUSIONS

MODY is a common cause of monogenic diabetes that constitutes 1% to 2% of all diabetes cases. Despite its low prevalence, identification of MODY genes has implications in diabetes pathogenesis. Various clinical characteristics of MODY can be explained by genetic heterogeneity. The advance of molecular genetics and clinical science has led to specific treatment for MODY subtypes. This is an excellent example of personalized medicine in the field of diabetes. Rapid MODY diagnosis is important for patients and their family members because it can provide for individualized treatment and prognosis predictions. However, diagnosing MODY is a challenge for physicians and the vast majority of cases remain unidentified. A nationwide MODY registry and systematic approaches are required for the rapid diagnosis and appropriate management of MODY.

NOTES

CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Tattersall RB. Mild familial diabetes with dominant inheritance. Q J Med 1974;43:339-357.
pmid
2. Ledermann HM. Maturity-onset diabetes of the young (MODY) at least ten times more common in Europe than previously assumed? Diabetologia 1995;38:1482
crossref
3. Vaxillaire M, Froguel P. Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocr Rev 2008;29:254-264.
crossref pmid
4. Kavvoura FK, Owen KR. Maturity onset diabetes of the young: clinical characteristics, diagnosis and management. Pediatr Endocrinol Rev 2012;10:234-242.
pmid
5. Hwang JS, Shin CH, Yang SW, Jung SY, Huh N. Genetic and clinical characteristics of Korean maturity-onset diabetes of the young (MODY) patients. Diabetes Res Clin Pract 2006;74:75-81.
crossref pmid
6. Hwang JS. MODY syndrome. J Korean Soc Pediatr Endocrinol 2010;15:1-6.
7. Nishigori H, Yamada S, Kohama T, Utsugi T, Shimizu H, Takeuchi T, Takeda J. Mutations in the hepatocyte nuclear factor-1 alpha gene (MODY3) are not a major cause of early-onset non-insulin-dependent (type 2) diabetes mellitus in Japanese. J Hum Genet 1998;43:107-110.
crossref pmid
8. Xu JY, Dan QH, Chan V, Wat NM, Tam S, Tiu SC, Lee KF, Siu SC, Tsang MW, Fung LM, Chan KW, Lam KS. Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients. Eur J Hum Genet 2005;13:422-427.
crossref pmid
9. Froguel P, Vaxillaire M, Sun F, Velho G, Zouali H, Butel MO, Lesage S, Vionnet N, Clement K, Fougerousse F, Tanizawa Y, Weissenbach J, Beckmann JS, Lathrop GM, Passa PH, Permutt MA, Cohen D. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 1992;356:162-164.
crossref
10. Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanne-Chantelot C, Ellard S, Gloyn 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.
crossref pmid
11. Yorifuji T, Fujimaru R, Hosokawa Y, Tamagawa N, Shiozaki M, Aizu K, Jinno K, Maruo Y, Nagasaka H, Tajima T, Kobayashi K, Urakami T. Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus. Pediatr Diabetes 2012;13:26-32.
crossref pmid
12. Feigerlova E, Pruhova S, Dittertova L, Lebl J, Pinterova D, Kolostova K, Cerna M, Pedersen O, Hansen T. Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents. Eur J Pediatr 2006;165:446-452.
crossref pmid
13. Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA 2014;311:279-286.
crossref
14. Kawakita R, Hosokawa Y, Fujimaru R, Tamagawa N, Urakami T, Takasawa K, Moriya K, Mizuno H, Maruo Y, Takuwa M, Nagasaka H, Nishi Y, Yamamoto Y, Aizu K, Yorifuji T. Molecular and clinical characterization of glucokinase maturity-onset diabetes of the young (GCK-MODY) in Japanese patients. Diabet Med 2014;31:1357-1362.
crossref
15. Hattersley A, Bruining J, Shield J, Njolstad P, Donaghue KC. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2009;10(Suppl 12):33-42.
crossref
16. Spyer G, Macleod KM, Shepherd M, Ellard S, Hattersley AT. Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabet Med 2009;26:14-18.
crossref
17. Dukes ID, Sreenan S, Roe MW, Levisetti M, Zhou YP, Ostrega D, Bell GI, Pontoglio M, Yaniv M, Philipson L, Polonsky KS. Defective pancreatic beta-cell glycolytic signaling in hepatocyte nuclear factor-1alpha-deficient mice. J Biol Chem 1998;273:24457-24464.
crossref pmid
18. Hattersley AT. Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity. Diabet Med 1998;15:15-24.
crossref
19. Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat 2013;34:669-685.
crossref pmid
20. Kim KA, Kang K, Chi YI, Chang I, Lee MK, Kim KW, Shoelson SE, Lee MS. Identification and functional characterization of a novel mutation of hepatocyte nuclear factor-1alpha gene in a Korean family with MODY3. Diabetologia 2003;46:721-727.
crossref pmid
21. Harries LW, Ellard S, Stride A, Morgan NG, Hattersley AT. Isomers of the TCF1 gene encoding hepatocyte nuclear factor-1 alpha show differential expression in the pancreas and define the relationship between mutation position and clinical phenotype in monogenic diabetes. Hum Mol Genet 2006;15:2216-2224.
crossref pmid
22. Pontoglio M, Prie D, Cheret C, Doyen A, Leroy C, Froguel P, Velho G, Yaniv M, Friedlander G. HNF1alpha controls renal glucose reabsorption in mouse and man. EMBO Rep 2000;1:359-365.
crossref pmid pmc
23. Steele AM, Shields BM, Shepherd M, Ellard S, Hattersley AT, Pearson ER. Increased all-cause and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A gene. Diabet Med 2010;27:157-161.
crossref pmid
24. Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet 2003;362:1275-1281.
crossref pmid
25. Shepherd M, Shields B, Ellard S, Rubio-Cabezas O, Hattersley AT. A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet Med 2009;26:437-441.
crossref pmid
26. Stoffel M, Duncan SA. The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci U S A 1997;94:13209-13214.
crossref pmid pmc
27. Pearson ER, Pruhova S, Tack CJ, Johansen A, Castleden HA, Lumb PJ, Wierzbicki AS, Clark PM, Lebl J, Pedersen O, Ellard S, Hansen T, Hattersley AT. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection. Diabetologia 2005;48:878-885.
crossref pmid
28. Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 2007;4:e118
crossref
29. Lehto M, Bitzen PO, Isomaa B, Wipemo C, Wessman Y, Forsblom C, Tuomi T, Taskinen MR, Groop L. Mutation in the HNF-4alpha gene affects insulin secretion and triglyceride metabolism. Diabetes 1999;48:423-425.
crossref pmid
30. Stoffers DA, Thomas MK, Habener JF. Homeodomain protein IDX-1: a master regulator of pancreas development and insulin gene expression. Trends Endocrinol Metab 1997;8:145-151.
crossref
31. Schwitzgebel VM, Mamin A, Brun T, Ritz-Laser B, Zaiko M, Maret A, Jornayvaz FR, Theintz GE, Michielin O, Melloul D, Philippe J. Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. J Clin Endocrinol Metab 2003;88:4398-4406.
crossref pmid
32. Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet 1997;17:138-139.
crossref
33. Coffinier C, Thepot D, Babinet C, Yaniv M, Barra J. Essential role for the homeoprotein vHNF1/HNF1beta in visceral endoderm differentiation. Development 1999;126:4785-4794.
pmid
34. Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn BN, Lindner T, Yamagata K, Ogata M, Tomonaga O, Kuroki H, Kasahara T, Iwamoto Y, Bell GI. Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet 1997;17:384-385.
crossref pmid
35. Edghill EL, Bingham C, Slingerland AS, Minton JA, Noordam C, Ellard S, Hattersley AT. Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1beta in human pancreatic development. Diabet Med 2006;23:1301-1306.
crossref pmid
36. Bellanne-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S, Wilhelm JM, Boitard C, Noel LH, Velho G, Timsit J. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med 2004;140:510-517.
crossref
37. Chen YZ, Gao Q, Zhao XZ, Chen YZ, Bennett CL, Xiong XS, Mei CL, Shi YQ, Chen XM. Systematic review of TCF2 anomalies in renal cysts and diabetes syndrome/maturity onset diabetes of the young type 5. Chin Med J (Engl) 2010;123:3326-3333.
pmid
38. Kim EK, Lee JS, Cheong HI, Chung SS, Kwak SH, Park KS. Identification and functional characterization of P159L mutation in HNF1B in a family with maturity-onset diabetes of the young 5 (MODY5). Genomics Inform 2014;12:240-246.
crossref
39. Ulinski T, Lescure S, Beaufils S, Guigonis V, Decramer S, Morin D, Clauin S, Deschenes G, Bouissou F, Bensman A, Bellanne-Chantelot C. Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol 2006;17:497-503.
crossref pmid
40. Pearson ER, Badman MK, Lockwood CR, Clark PM, Ellard S, Bingham C, Hattersley AT. Contrasting diabetes phenotypes associated with hepatocyte nuclear factor-1alpha and -1beta mutations. Diabetes Care 2004;27:1102-1107.
crossref
41. Malecki MT, Jhala US, Antonellis A, Fields L, Doria A, Orban T, Saad M, Warram JH, Montminy M, Krolewski AS. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet 1999;23:323-328.
crossref pmid
42. Gonsorcikova L, Pruhova S, Cinek O, Ek J, Pelikanova T, Jorgensen T, Eiberg H, Pedersen O, Hansen T, Lebl J. Autosomal inheritance of diabetes in two families characterized by obesity and a novel H241Q mutation in NEUROD1. Pediatr Diabetes 2008;9(4 Pt 2):367-372.
crossref pmid
43. Rubio-Cabezas O, Minton JA, Kantor I, Williams D, Ellard S, Hattersley AT. Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes 2010;59:2326-2331.
crossref pmid pmc
44. Fernandez-Zapico ME, van Velkinburgh JC, Gutierrez-Aguilar R, Neve B, Froguel P, Urrutia R, Stein R. MODY7 gene, KLF11, is a novel p300-dependent regulator of Pdx-1 (MODY4) transcription in pancreatic islet beta cells. J Biol Chem 2009;284:36482-36490.
crossref pmid pmc
45. Neve B, Fernandez-Zapico ME, Ashkenazi-Katalan V, Dina C, Hamid YH, Joly E, Vaillant E, Benmezroua Y, Durand E, Bakaher N, Delannoy V, Vaxillaire M, Cook T, Dallinga-Thie GM, Jansen H, Charles MA, Clement K, Galan P, Hercberg S, Helbecque N, Charpentier G, Prentki M, Hansen T, Pedersen O, Urrutia R, Melloul D, Froguel P. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. Proc Natl Acad Sci U S A 2005;102:4807-4812.
crossref pmid pmc
46. Raeder H, Johansson S, Holm PI, Haldorsen IS, Mas E, Sbarra V, Nermoen I, Eide SA, Grevle L, Bjorkhaug L, Sagen JV, Aksnes L, Sovik O, Lombardo D, Molven A, Njolstad PR. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet 2006;38:54-62.
crossref pmid
47. Johansson BB, Torsvik J, Bjorkhaug L, Vesterhus M, Ragvin A, Tjora E, Fjeld K, Hoem D, Johansson S, Raeder H, Lindquist S, Hernell O, Cnop M, Saraste J, Flatmark T, Molven A, Njolstad PR. 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;286:34593-34605.
crossref
48. Plengvidhya N, Kooptiwut S, Songtawee N, Doi A, Furuta H, Nishi M, Nanjo K, Tantibhedhyangkul W, Boonyasrisawat W, Yenchitsomanus PT, Doria A, Banchuin N. PAX4 mutations in Thais with maturity onset diabetes of the young. J Clin Endocrinol Metab 2007;92:2821-2826.
crossref pmid
49. Mauvais-Jarvis F, Smith SB, Le May C, Leal SM, Gautier JF, Molokhia M, Riveline JP, Rajan AS, Kevorkian JP, Zhang S, Vexiau P, German MS, Vaisse C. PAX4 gene variations predispose to ketosis-prone diabetes. Hum Mol Genet 2004;13:3151-3159.
crossref pmid pmc
50. Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A, Shields B, Shepherd MH, Hussain K, Kapoor RR, Malecki M, MacDonald MJ, Stoy J, Steiner DF, Philipson LH, Bell GI, Hattersley AT, Ellard S. Neonatal Diabetes International Collaborative Group. 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 2008;57:1034-1042.
crossref pmid
51. Meur G, Simon A, Harun N, Virally M, Dechaume A, Bonnefond A, Fetita S, Tarasov AI, Guillausseau PJ, Boesgaard TW, Pedersen O, Hansen T, Polak M, Gautier JF, Froguel P, Rutter GA, Vaxillaire M. Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention. Diabetes 2010;59:653-661.
crossref pmid
52. Borowiec M, Liew CW, Thompson R, Boonyasrisawat W, Hu J, Mlynarski WM, El Khattabi I, Kim SH, Marselli L, Rich SS, Krolewski AS, Bonner-Weir S, Sharma A, Sale M, Mychaleckyj JC, Kulkarni RN, Doria A. Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. Proc Natl Acad Sci U S A 2009;106:14460-14465.
crossref pmid pmc
53. Kim SH, Ma X, Weremowicz S, Ercolino T, Powers C, Mlynarski W, Bashan KA, Warram JH, Mychaleckyj J, Rich SS, Krolewski AS, Doria A. Identification of a locus for maturity-onset diabetes of the young on chromosome 8p23. Diabetes 2004;53:1375-1384.
crossref pmid
54. Bowman P, Flanagan SE, Edghill EL, Damhuis A, Shepherd MH, Paisey R, Hattersley AT, Ellard S. Heterozygous ABCC8 mutations are a cause of MODY. Diabetologia 2012;55:123-127.
crossref pmid
55. Bonnefond A, Philippe J, Durand E, Dechaume A, Huyvaert M, Montagne L, Marre M, Balkau B, Fajardy I, Vambergue A, Vatin V, Delplanque J, Le Guilcher D, De Graeve F, Lecoeur C, Sand O, Vaxillaire M, Froguel P. Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS One 2012;7:e37423
crossref
56. Liu L, Nagashima K, Yasuda T, Liu Y, Hu HR, He G, Feng B, Zhao M, Zhuang L, Zheng T, Friedman TC, Xiang K. Mutations in KCNJ11 are associated with the development of autosomal dominant, early-onset type 2 diabetes. Diabetologia 2013;56:2609-2618.
crossref
57. Shim YJ, Kim JE, Hwang SK, Choi BS, Choi BH, Cho EM, Jang KM, Ko CW. Identification of candidate gene variants in Korean MODY families by whole-exome sequencing. Horm Res Paediatr 2015;83:242-251.
crossref pmid
58. Lee HJ, Ahn CW, Kim SJ, Song YD, Lim SK, Kim KR, Lee HC, Huh KB. Mutation in hepatocyte nuclear factor-1alpha is not a common cause of MODY and early-onset type 2 diabetes in Korea. Acta Diabetol 2001;38:123-127.
crossref pmid
59. Choi IK, Kim DH, Kim HS, Huh N, Paek SH, Jung SY. The prevalence of maturity onset diabetes of the young (MODY) 3 in children with type 2 diabetes mellitus. Korean J Pediatr 2004;47:641-646.
60. Lim DM, Huh N, Park KY. Hepatocyte nuclear factor 1-alpha mutation in normal glucose-tolerant subjects and early-onset type 2 diabetic patients. Korean J Intern Med 2008;23:165-169.
crossref pmid pmc
61. Kim HS, Hwang SH, Choi ES, Park SY, Yim CH, Han KO, Yoon HK, Chung HY, Kim KS, Bok J, Lee JY, Kim SH. Mutation screening of HNF-1alpha gene in Korean women with gestational diabetes mellitus. Korean Diabetes J 2008;32:38-43.
crossref
62. Ellard S, Lango Allen H, De Franco E, Flanagan SE, Hysenaj G, Colclough K, Houghton JA, Shepherd M, Hattersley AT, Weedon MN, Caswell R. Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia 2013;56:1958-1963.
crossref pmid pmc
63. Johansson S, Irgens H, Chudasama KK, Molnes J, Aerts J, Roque FS, Jonassen I, Levy S, Lima K, Knappskog PM, Bell GI, Molven A, Njolstad PR. Exome sequencing and genetic testing for MODY. PLoS One 2012;7:e38050
crossref pmid pmc
64. Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 2010;53:2504-2508.
crossref
65. Thanabalasingham G, Pal A, Selwood MP, Dudley C, Fisher K, Bingley PJ, Ellard S, Farmer AJ, McCarthy MI, Owen KR. Systematic assessment of etiology in adults with a clinical diagnosis of young-onset type 2 diabetes is a successful strategy for identifying maturity-onset diabetes of the young. Diabetes Care 2012;35:1206-1212.
crossref
66. Shields BM, McDonald TJ, Ellard S, Campbell MJ, Hyde C, Hattersley AT. 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.
crossref pmid pmc
67. Owen KR, Thanabalasingham G, James TJ, Karpe F, Farmer AJ, McCarthy MI, Gloyn AL. Assessment of high-sensitivity C-reactive protein levels as diagnostic discriminator of maturity-onset diabetes of the young due to HNF1A mutations. Diabetes Care 2010;33:1919-1924.
crossref pmid pmc
68. McDonald TJ, Shields BM, Lawry J, Owen KR, Gloyn AL, Ellard S, Hattersley AT. High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes. Diabetes Care 2011;34:1860-1862.
crossref
69. Thanabalasingham G, Shah N, Vaxillaire M, Hansen T, Tuomi T, Gasperikova D, Szopa M, Tjora E, James TJ, Kokko P, Loiseleur F, Andersson E, Gaget S, Isomaa B, Nowak N, Raeder H, Stanik J, Njolstad PR, Malecki MT, Klimes I, Groop L, Pedersen O, Froguel P, McCarthy MI, Gloyn AL, Owen KR. A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes. Diabetologia 2011;54:2801-2810.
crossref pmid
70. Bonner C, Nyhan KC, Bacon S, Kyithar MP, Schmid J, Concannon CG, Bray IM, Stallings RL, Prehn JH, Byrne MM. Identification of circulating microRNAs in HNF1A-MODY carriers. Diabetologia 2013;56:1743-1751.
crossref pmid
Fig. 1

Diagnostic algorithm for maturity-onset diabetes of the young (MODY). T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

dmj-39-468-g001.jpg
Table 1

Clinical and molecular characteristics of MODY subtypes

MODY, maturity-onset diabetes of the young; HNF4A, hepatocyte nuclear factor 4 α; GCK, glucokinase; PDX1, pancreatic and duodenal homeobox 1; IPF1, insulin promoter factor 1; OAD, oral antidiabetic agents; NEUROD1, neurogenic differentiation 1; KLF11, Kruppel-like factor 11; CEL, carboxyl ester lipase; PAX4, paired-box-containing gene 4; INS, insulin; PNDM, permanent neonatal diabetes; BLK, B-lymphocyte kinase; ABCC8, ATP-binding cassette, subfamily C (CFTR/MRP), member 8; ATP, adenosine triphosphate; KCNJ11, potassium channel, inwardly rectifying subfamily J, member 11.

MODY gene Chromosomal location Frequency (% from MODYs) Pathophysiology Other features Treatment
HNF4A 20q13 5 β-Cell dysfunction Neonatal hyperinsulinemia, low triglycerides Sensitive to sulfonylurea
GCK 7p13 15-20 β-Cell dysfunction (glucose sensing defect) Fasting hyperglycemia from newborn Diet
HNF1A 12q24 30-50 β-Cell dysfunction Glycosuria Sensitive to sulfonylurea
PDX1/IPF1 13q12 <1 β-Cell dysfunction Homozygote: pancreatic agenesis Diet or OAD or insulin
HNF1B 17q12 5 β-Cell dysfunction Renal anomalies, genital anomalies, pancreatic hypoplasia insulin
NEUROD1 2q31 <1 β-Cell dysfunction Adult onset diabetes OAD or insulin
KLF11 2p25 <1 β-Cell dysfunction Similar to type 2 diabetes mellitus OAD or insulin
CEL 9q34 <1 Pancreas endocrine and exocrine dysfunction Exocrine insufficiency, lipomatosis OAD or insulin
PAX4 7q32 <1 β-Cell dysfunction Possible ketoacidosis Diet or OAD or insulin
INS 11p15 <1 Insulin gene mutation Can also present PNDM OAD or insulin
BLK 8p23 <1 Insulin secretion defect Overweight, relative insulin secretion defect Diet or OAD or insulin
ABCC8 11p15 <1 ATP-sensitive potassium channel dysfunction Homozygote: permanent neonatal diabetes; heterozygote: transient neonatal diabetes OAD (sulfonylurea)
KCNJ11 11p15 <1 ATP-sensitive potassium channel dysfunction Homozygote: neonatal diabetes Diet or OAD or insulin
Table 2

MODY studies in Korean subjects

MODY, maturity-onset diabetes of the young; HNF1A, hepatocyte nuclear factor 1 α; T2DM, type 2 diabetes mellitus; GCK, glucokinase; GDM, gestational diabetes mellitus; PTPRD, protein tyrosine phosphatase, receptor type, D; SYT9, synaptotagmin-9; WFS1, Wolfram syndrome 1.

Gene Subjects Finding Reference
HNF1A 69 early onset T2DM One silent mutation [58]
HNF1A 16 early onset T2DM One missense (R236L) mutation [20]
HNF1A 22 early onset T2DM One mutation (promoter) [59]
HNF4A, GCK, HNF1A 23 MODY and 17 early onset T2DM One HNF1A (P393fsdelC, promoter) [5]
One GCK (R191W)
One HNF4A (T130I polymorphism)
HNF1A 25 early-onset T2DM Four promoter polymorphism [60]
HNF1A 96 GDM Five mutations ( 2 promoter, Arg278Gln, Pro300pro, IVS5 + 106A>G) [62]
HNF1B 1 MODY One missense (P159L) mutation [38]
PTPRD, SYT9, WFS1 6 MODY Thr207Ile in PTPRD, Gln187Glu in SYT9, Val509Gly in WFS1 by whole-exome sequencing [57]
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