Delineation of the genetic and clinical spectrum, including candidate genes, of monogenic diabetes: a multicenter study in South Korea
-
Chong Kun Cheon
,
Yeoun Joo Lee
Abstract
Objectives
Monogenic diabetes includes a group of heterogeneous diabetes types. We aimed to identify the frequency, clinical and molecular features of monogenic diabetes in a Korean pediatric cohort.
Methods
A retrospective cohort and multicenter study of Korean children suspected to have monogenic diabetes, managed by four pediatric endocrine centers in the southeast region of South Korea, from February 2016 to February 2020. We recruited 27 pediatric Korean patients suspected to have monogenic diabetes who had at least two of the following three criteria (age at diagnosis, family history, and clinical presentation). Targeted exome sequencing was conducted in these patients. The functional consequences of the variants were predicted by bioinformatics and protein structure analysis.
Results
Molecular genetic analysis identified 16 patients (59.3%) with monogenic diabetes. We identified a total of eight unique variants, including five novel variants (HNF4A c.1088C>T, CEL c.1627C>T and c.1421C>T, PAX4 c.538+8G>C, INS c.71C>T). We also identified two potential candidate gene variants for monogenic diabetes, namely c.650T>C in the SLC2A2 gene and c.629G>A in the PTF1A gene. Other variants were identified in the WFS1and NPHP3 genes in two rare genetic disorders. Variant-positive individuals had a lower presence of autoantibody positivity at the time of diagnosis and higher glycosylated hemoglobin levels at last follow-up when compared to variant-negative patients (p<0.001 and p=0.029, respectively).
Conclusions
These results further expand the spectrum of known variants as well as potential candidate gene variants associated with monogenic diabetes in Korea.
Funding source: Pusan National University
Acknowledgments
We gratefully acknowledge the cooperation of the patients and their families. Finally, we would like to thank Editage (www.editage.co.kr) for English language editing.
Research funding: This work was supported by a 2-year Research Grant of the Pusan National University.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Written informed consent for the study was obtained from all study participants.
Ethical approval: This study was approved by the Institutional Review Board of our Institution and conducted according to the Declaration of Helsinki. All parents of the children and/or the patients gave their written informed consent authorizing the use of their medical records for research purposes.
References
1. Harris, A, Naylor, RN. Pediatric monogenic diabetes: a unique challenge and opportunity. Pediatr Ann 2019;48:e319–25, https://doi.org/10.3928/19382359-20190730-02.Search in Google Scholar
2. Alkorta-Aranburu, G, Carmody, D, Cheng, YW, Nelakuditi, V, Ma, L, Dickens, JT, et al. Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach. Mol Genet Metabol 2014;113:315–20, https://doi.org/10.1016/j.ymgme.2014.09.007.Search in Google Scholar
3. Yang, Y, Chan, L. Monogenic diabetes: what it teaches us on the common forms of type 1 and type 2 diabetes. Endocr Rev 2016;37:190–222, https://doi.org/10.1210/er.2015-1116.Search in Google Scholar
4. Astuti, D, Sabir, A, Fulton, P, Zatyka, M, Williams, D, Hardy, C, et al. Monogenic diabetes syndromes: locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia. Hum Mutat 2017;38:764–77, https://doi.org/10.1002/humu.23233.Search in Google Scholar
5. Gardner, DS, Tai, ES. Clinical features and treatment of maturity onset diabetes of the young (MODY). Diabetes Metab Syndr Obes 2012;5:101–8, https://doi.org/10.2147/dmso.s23353.Search in Google Scholar
6. Bonnefond, A, Philippe, J, Durand, E, Muller, J, Saeed, S, Arslan, M, et al. Highly sensitive diagnosis of 43 monogenic forms of diabetes or obesity through one-step PCR-based enrichment in combination with next-generation sequencing. Diabetes Care 2014;37:460–7, https://doi.org/10.2337/dc13-0698.Search in Google Scholar
7. 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, https://doi.org/10.1038/gim.2015.30.Search in Google Scholar
8. DeLano, WL. The PyMOL Molecular Graphics System; 2002. San Carlos, CA: DeLano Scientific. Available from: https://pymol.org/2/.Search in Google Scholar
9. Urakami, T. Maturity-onset diabetes of the young (MODY): current perspectives on diagnosis and treatment. Diabetes Metab Syndr Obes 2019;12:1047–56, https://doi.org/10.2147/dmso.s179793.Search in Google Scholar
10. Yorifuji, T, Fujimaru, R, Hosokawa, Y, Tamagawa, N, Shiozaki, M, Aizu, K, et al. Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus. Pediatr Diabetes 2012;13:26–32, https://doi.org/10.1111/j.1399-5448.2011.00827.x.Search in Google Scholar
11. Sosa-Pineda, B. The gene Pax4 is an essential regulator of pancreatic beta-cell development. Mol Cell 2004;18:289–94.10.1016/S1016-8478(23)13114-1Search in Google Scholar
12. Shimajiri, Y, Sanke, T, Furuta, H, Hanabusa, T, Nakagawa, T, Fujitani, Y, et al. A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese. Diabetes 2001; 50:2864–9, https://doi.org/10.2337/diabetes.50.12.2864.Search in Google Scholar
13. Michau, A, Guillemain, G, Grosfeld, A, Vuillaumier-Barrot, S, Grand, T, Keck, M, et al. Mutations in SLC2A2 gene reveal hGLUT2 function in pancreatic β cell development. J Biol Chem 2013;288:31080–92, https://doi.org/10.1074/jbc.m113.469189.Search in Google Scholar
14. Thorens, B. GLUT2, glucose sensing and glucose homeostasis. Diabetologia 2015;58:221–32, https://doi.org/10.1007/s00125-014-3451-1.Search in Google Scholar
15. Vallianou, NG, Kazazis, C, Ioannidis, G. Diabetic hepatosclerosis: true clinical entity or ghost disease? Diabetes Metab Syndr 2017;11(Suppl 2):S775–6, https://doi.org/10.1016/j.dsx.2017.05.015.Search in Google Scholar
16. Kouidhi, S, Berrhouma, R, Rouissi, K, Jarboui, S, Clerget-Froidevaux, MS, Seugnet, I, et al. Human subcutaneous adipose tissue Glut 4 mRNA expression in obesity and type 2 diabetes. Acta Diabetol 2013;50:227–32, https://doi.org/10.1007/s00592-011-0295-8.Search in Google Scholar
17. Quistgaard, EM, Löw, C, Guettou, F, Nordlund, P. Understanding transport by the major facilitator superfamily (MFS): structures pave the way. Nat Rev Mol Cell Biol 2016;17:123–32, https://doi.org/10.1038/nrm.2015.25.Search in Google Scholar
18. Kawaguchi, Y, Cooper, B, Gannon, M, Ray, M, MacDonald, RJ, Wright, CV. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat Genet 2002;32:128–34, https://doi.org/10.1038/ng959.Search in Google Scholar
19. Sakikubo, M, Furuyama, K, Horiguchi, M, Hosokawa, S, Aoyama, Y, Tsuboi, K, et al. Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway. Sci Rep 2018;8:15812, https://doi.org/10.1038/s41598-018-34093-4.Search in Google Scholar
20. Masui, T, Long, Q, Beres, TM, Magnuson, MA, MacDonald, RJ. Early pancreatic development requires the vertebrate suppressor of hairless (RBPJ) in the PTF1 bHLH complex. Genes Dev 2007;21:2629–43, https://doi.org/10.1101/gad.1575207.Search in Google Scholar
21. Takeda, K, Inoue, H, Tanizawa, Y, Matsuzaki, Y, Oba, J, Watanabe, Y, et al. WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum Mol Genet 2001;10:477–84, https://doi.org/10.1093/hmg/10.5.477.Search in Google Scholar
22. Yamamoto, H, Hofmann, S, Hamasaki, DI, Yamamoto, H, Kreczmanski, P, Schmitz, C, et al. Wolfram Syndrome 1 (WFS1) protein expression in retinal ganglion cells and optic nerve glia of the cynomolgus monkey. Exp Eye Res 2006;83:1303–6, https://doi.org/10.1016/j.exer.2006.06.010.Search in Google Scholar
23. Gómez-Zaera, M, Strom, TM, Rodríguez, B, Estivill, X, Meitinger, T, Nunes, V. Presence of a major WFS1 mutation in Spanish Wolfram syndrome pedigrees. Mol Genet Metabol 2001;72: 72–81, https://doi.org/10.1006/mgme.2000.3107.Search in Google Scholar
24. Olbrich, H, Fliegauf, M, Hoefele, J, Kispert, A, Otto, E, Volz, A, et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nat Genet 2003;34:455–9, https://doi.org/10.1038/ng1216.Search in Google Scholar
25. Simms, RJ, Eley, L, Sayer, JA. Nephronophthisis. Eur J Hum Genet 2009;17:406–16, https://doi.org/10.1038/ejhg.2008.238.Search in Google Scholar
26. Grabski, R, Balklava, Z, Wyrozumska, P, Szul, T, Brandon, E, Alvarez, C, et al. Identification of a functional domain within the p115 tethering factor that is required for Golgi ribbon assembly and membrane trafficking. J Cell Sci 2012;125:1896–909, https://doi.org/10.1242/jcs.090571.Search in Google Scholar
27. Park, SS, Jang, SS, Ahn, CH, Kim, JH, Jung, HS, Cho, YM, et al. Identifying pathogenic variants of monogenic diabetes using targeted panel sequencing in an East Asian population. J Clin Endocrinol Metab 2019 Apr 12. https://doi.org/10.1210/jc-2018-02397 [Epub ahead of print].Search in Google Scholar
28. Guazzini, B, Gaffi, D, Mainieri, D, Multari, G, Cordera, R, Bertolini, S, et al. Three novel missense mutations in the glucokinase gene (G80S; E221K; G227C) in Italian subjects with maturity-onset diabetes of the young (MODY). Mutations in brief no. 162. Online. Hum Mutat 1998;12:136, https://doi.org/10.1002/(sici)1098-1004(1998)12:2<136::aid-humu13>3.0.co;2-v.10.1002/(SICI)1098-1004(1998)12:2<136::AID-HUMU13>3.0.CO;2-VSearch in Google Scholar
29. Colclough, K, Saint-Martin, C, Timsit, J, Ellard, S, Bellanné-Chantelot, C. Clinical utility gene card for: maturity-onset diabetes of the young. Eur J Hum Genet 2014 Sep 22. https://doi.org/10.1038/ejhg.2014.14 [Epub ahead of print].Search in Google Scholar
30. Dimova, R, Tankova, T, Gergelcheva, I, Tournev, I, Konstantinova, M. A family with permanent neonatal diabetes due to a novel mutation in INS gene. Diabetes Res Clin Pract 2015;108:e28–30, https://doi.org/10.1016/j.diabres.2015.02.021.Search in Google Scholar
31. Rees, MG, Ng, D, Ruppert, S, Turner, C, Beer, NL, Swift, AJ, et al. Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes. J Clin Invest 2012;122:205–17, https://doi.org/10.1172/jci46425.Search in Google Scholar
32. Sandhu, MS, Weedon, MN, Fawcett, KA, Wasson, J, Debenham, SL, Daly, A, et al. Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet 2007;39:951–3, https://doi.org/10.1038/ng2067.Search in Google Scholar
33. Zeng, W, Peng, J, Wan, X, Chen, S, Song, H. The mutation of insulin receptor substrate-1 gene in Chinese patients with non-insulin-dependent diabetes mellitus. Chin Med J (Engl) 2000;113: 80–3, https://doi.org/10.3901/jme.2000.11.080.Search in Google Scholar
© 2020 Walter de Gruyter GmbH, Berlin/Boston
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Articles in the same Issue
- Frontmatter
- Review Article
- Papillary thyroid carcinoma in children with Hashimoto’s thyroiditis – a review of the literature between 2000 and 2020
- Original Articles
- Tyrosine metabolism in health and disease: slow-release amino acids therapy improves tyrosine homeostasis in phenylketonuria
- Evolution of Hashimoto thyroiditis in children with type 1 diabetes mellitus (TIDM)
- Glycated hemoglobin variability and microvascular complications in patients with type 1 diabetes mellitus
- Delineation of the genetic and clinical spectrum, including candidate genes, of monogenic diabetes: a multicenter study in South Korea
- Can we use copeptin as a biomarker for masked hypertension or metabolic syndrome in obese children and adolescents?
- Relationship of acanthosis nigricans with metabolic syndrome in obese children
- Daily intake of macronutrients and energy in childhood and its association with cardiometabolic risk factors in Colombians
- The effect of treatment with recombinant human growth hormone (rhGH) on linear growth and adult height in children with idiopathic short stature (ISS): a systematic review and meta-analysis
- Growth in achondroplasia, from birth to adulthood, analysed by the JPA-2 model
- Short Communication
- Assessing disparities in barriers to attending pediatric diabetes camp
- Letter to the Editor
- Severity in pediatric type 1 diabetes mellitus debut during the COVID-19 pandemic
- Case Reports
- The use of glimepiride for the treatment of neonatal diabetes mellitus caused by a novel mutation of the ABCC8 gene
- Effect of recombinant human insulin-like growth factor 1 therapy in a child with 3-M syndrome-1 with CUL7 gene mutation
- A nonsense variant in FGFR1: a rare cause of combined pituitary hormone deficiency
- Treatment response to long term antiresorptive therapy in osteogenesis imperfecta type VI: does genotype matter?
