Skip to main content
SpringerLink
Log in

Partial GCK gene deletion mutations causing maturity-onset diabetes of the young

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

Aims

Maturity-onset diabetes of the young (MODY) is an autosomal dominant monogenic form of diabetes, and glucokinase-maturity-onset diabetes of the young (GCK-MODY), or MODY 2, being the most prevalent type. However, the presence of copy number variants (CNVs) may lead to misdiagnoses, as genetic testing for MODY is typically reliant on sequencing techniques. This study aimed to describe the process of diagnosis in a Chinese pedigree with an exon 8–10 deletion of the GCK gene.

Methods

This study collected clinical data and medical history through direct interviews with the patient and reviewing relevant medical records. Sanger sequencing and whole exome sequencing (WES) were conducted over years of follow up. WES-based CNV sequencing technology was used to detect CNVs and the results were validated by multiplex ligation-dependent amplification dosage assay (MLPA). Additionally, we reviewed the previously reported cases caused by heterozygous exon deletion of the GCK gene.

Results

WES-based CNV detection revealed a heterozygous exon 8–10 deletion in the GCK gene within this particular pedigree after Sanger sequencing and WES failed to find causal variants in single nucleotide variations (SNVs) and small indels. The deletion was considered pathogenic according to ACMG/AMP and ClinGen guidelines. Most of the previously reported cases caused by heterozygous exon deletion or whole gene deletion of the GCK gene present similarly to GCK-MODY caused by SNVs and small indels.

Conclusions

This study contributed to progress in our comprehension of the mutation spectrum of the GCK gene and underscored the significance of CNV detection in the genetic testing of MODY.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ellard S, Thomas K, Edghill EL et al (2007) Partial and whole gene deletion mutations of the GCK and HNF1A genes in maturity-onset diabetes of the young. Diabetologia 50(11):2313–2317. https://doi.org/10.1007/s00125-007-0798-6

    Article  CAS  PubMed  Google Scholar 

  2. Wang X, Lam SM, Cao M et al (2021) Localized increases in CEPT1 and ATGL elevate plasmalogen phosphatidylcholines in HDLs contributing to atheroprotective lipid profiles in hyperglycemic GCK-MODY. Redox Biol 40:101855. https://doi.org/10.1016/j.redox.2021.101855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Berberich AJ, Huot C, Cao H et al (2019) Copy number variation in GCK in patients with maturity-onset diabetes of the young. J Clin Endocrinol Metab 104(8):3428–3436. https://doi.org/10.1210/jc.2018-02574

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zhang B, Feng Z, Zhang L (1998) A study on the physical development of newborns of different gestational ages in 15 cities in China. Chin J Pediatr 26(4):206–208

    Google Scholar 

  5. Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164–e164. https://doi.org/10.1093/nar/gkq603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kamata K, Mitsuya M, Nishimura T, Eiki J, Nagata Y (2004) Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure 12(3):429–438. https://doi.org/10.1016/j.str.2004.02.005

    Article  CAS  PubMed  Google Scholar 

  7. Concolino P, Tartaglione L, De Paolis E et al (2022) A novel GCK large genomic rearrangement in a patient with MODY-2 detected by clinical exome sequencing. Genes 13(11):2104. https://doi.org/10.3390/genes13112104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT (2014) Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA 311(3):279. https://doi.org/10.1001/jama.2013.283980

    Article  CAS  PubMed  Google Scholar 

  9. Birkebæk NH, Sørensen JS, Vikre-Jørgensen J, Jensen PKA, Pedersen O, Hansen T (2011) A De Novo whole GCK gene deletion not detected by gene sequencing, in a boy with phenotypic GCK insufficiency. Case Rep Genet 2011:1–3. https://doi.org/10.1155/2011/768610

    Article  Google Scholar 

  10. Zhang H, Colclough K, Gloyn AL, Pollin TI (2021) Monogenic diabetes: a gateway to precision medicine in diabetes. J Clin Invest 131(3):e142244. https://doi.org/10.1172/JCI142244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bitterman O, Tinto N, Franzese A et al (2018) Glucokinase deficit and birthweight: does maternal hyperglycemia always meet fetal needs? Acta Diabetol 55(12):1247–1250. https://doi.org/10.1007/s00592-018-1198-8

    Article  CAS  PubMed  Google Scholar 

  12. De Las HJ, Martínez R, Rica I et al (2010) Heterozygous glucokinase mutations and birth weight in Spanish children: letters. Diabet Med 27(5):608–610. https://doi.org/10.1111/j.1464-5491.2010.02953.x

    Article  Google Scholar 

  13. López Tinoco C, Sánchez Lechuga B, Bacon S et al (2021) Evaluation of pregnancy outcomes in women with GCK-MODY. Diabet Med. https://doi.org/10.1111/dme.14488

    Article  PubMed  Google Scholar 

  14. Spyer G, Macleod KM, Shepherd M, Ellard S, Hattersley AT (2009) Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabet Med 26(1):14–18. https://doi.org/10.1111/j.1464-5491.2008.02622.x

    Article  CAS  PubMed  Google Scholar 

  15. Stride A, Shields B, Gill-Carey O et al (2014) Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia 57(1):54–56. https://doi.org/10.1007/s00125-013-3075-x

    Article  CAS  PubMed  Google Scholar 

  16. Carmody D, Naylor RN, Bell CD et al (2016) GCK-MODY in the US national monogenic diabetes registry: frequently misdiagnosed and unnecessarily treated. Acta Diabetol 53(5):703–708. https://doi.org/10.1007/s00592-016-0859-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shields BM, McDonald TJ, Ellard S, Campbell MJ, Hyde C, Hattersley AT (2012) The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes. Diabetologia 55(5):1265–1272. https://doi.org/10.1007/s00125-011-2418-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fu J, Ping F, Wang T et al (2021) A clinical prediction model to distinguish maturity-onset diabetes of the young from type 1 and type 2 diabetes in the chinese population. Endocr Pract 27(8):776–782. https://doi.org/10.1016/j.eprac.2021.05.002

    Article  PubMed  Google Scholar 

  19. Zhang H, Kleinberger JW, Maloney KA et al (2022) Model for integration of monogenic diabetes diagnosis into routine care: the personalized diabetes medicine program. Diabetes Care 45(8):1799–1806. https://doi.org/10.2337/dc21-1975

    Article  PubMed  PubMed Central  Google Scholar 

  20. Pinelli M, Acquaviva F, Barbetti F, Caredda E, Cocozza S, Delvecchio M, Italian Study Group on Diabetes of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED). (2013) Identification of candidate children for maturity-onset diabetes of the young type 2 (MODY2) gene testing: a seven-item clinical flowchart (7-iF). PLoS One, 8(11): e79933

  21. Chakera AJ, Steele AM, Gloyn AL et al (2015) Recognition and management of individuals with hyperglycemia because of a heterozygous glucokinase mutation. Diabetes Care 38(7):1383–1392. https://doi.org/10.2337/dc14-2769

    Article  CAS  PubMed  Google Scholar 

  22. Garin I, Rica I, Estalella I et al (2008) Haploinsufficiency at GCK gene is not a frequent event in MODY2 patients. Clin Endocrinol (Oxf) 68(6):873–878. https://doi.org/10.1111/j.1365-2265.2008.03214.x

    Article  CAS  PubMed  Google Scholar 

  23. Yorifuji T, Fujimaru R, Hosokawa Y et al (2012) Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus. Pediatr Diabetes 13(1):26–32. https://doi.org/10.1111/j.1399-5448.2011.00827.x

    Article  CAS  PubMed  Google Scholar 

  24. Kawakita R, Hosokawa Y, Fujimaru R et al (2014) Molecular and clinical characterization of glucokinase maturity-onset diabetes of the young (GCK-MODY) in Japanese patients. Diabet Med 31(11):1357–1362. https://doi.org/10.1111/dme.12487

    Article  CAS  PubMed  Google Scholar 

  25. Katashima R, Matsumoto M, Watanabe Y, Moritani M, Yokota I (2021) Identification of novel GCK and HNF4α gene variants in japanese pediatric patients with onset of diabetes before 17 years of age. J Diabetes Res. https://doi.org/10.1155/2021/7216339

    Article  PubMed  PubMed Central  Google Scholar 

  26. Trhanint S, Bouguenouch L, Abourazzak S et al (2022) Molecular and clinical assessment of maturity-onset diabetes of the young revealed low mutational rate in Moroccan families. Int J Pediatr Adolesc Med 9(2):98–103. https://doi.org/10.1016/j.ijpam.2021.03.006

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the participants in this study.

Funding

This work was supported by the grants from National Natural Science Foundation of China (No. 82170854, 81870579, 81870545, 81570715, 81170736), Beijing Natural Science Foundation (7202163), Beijing Municipal Science & Technology Commission (Z201100005520011), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-019, 2022-PUMCH-B-121), National Key Research and Development Program of China (2018YFC2001100), CAMS Innovation Fund for Medical Sciences (CIFMS2021-1-I2M-002, CIFMS2017-I2M-1–008).

Author information

Authors and Affiliations

  1. Key Laboratory of Endocrinology of National Health Commission, Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China

    Ruiqi Yu, Haichen Zhang & Xinhua Xiao

  2. The Beijing Genomics Institute-Research, Beijing, 100101, China

    Haichen Zhang

Authors
  1. Ruiqi Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haichen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xinhua Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RY analyzed the clinical data and wrote the manuscript. HZ contributed with gene analysis and was a major contributor to the writing of the manuscript. XX was contributed to acquisition and interpretation of the data, and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Xinhua Xiao.

Ethics declarations

Conflicts of interest

The authors declare no conflict of interest.

Ethical approval

The study was approved by the ethics committee of Peking Union Medical College Hospital, China. The reference number is K2985, and the date of approval is 2023–3-13.

Informed consent

Guardian provided informed consent for genetic testing and analysis.

Human and animal rights

Informed consent was provided by the patient.

Additional information

Managed by Fabrizio Barbetti.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 15 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, R., Zhang, H. & Xiao, X. Partial GCK gene deletion mutations causing maturity-onset diabetes of the young. Acta Diabetol 61, 107–115 (2024). https://doi.org/10.1007/s00592-023-02173-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-023-02173-1

Keywords

Search

Navigation