Skip to main content
SpringerLink
Log in

Identification of novel polymorphisms in the glucokinase and glucose-6-phosphatase genes in infants who died suddenly and unexpectedly

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Sudden and unexpected infant deaths can be unexplained [sudden infant death syndrome (SIDS)] or explained (non-SIDS) but risk factors including lower birthweight are similar in both groups. Mutations in the glucokinase (GK) gene result in Maturity Onset Diabetes of the Young type 2 (MODY 2) and are associated with lower birthweight. Low hepatic glucose-6-phosphatase (G6PC1) expression occurs in both low birthweight and SIDS infants. We investigated whether polymorphisms are prevalent in the GK and G6PC1 genes in infants who died suddenly and unexpectedly. Mutation analysis was performed by polymerase chain reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC) in samples from 126 infants who died suddenly and unexpectedly (78 SIDS, 48 non-SIDS) and from 70 healthy, living infants. G6PC1 promoter polymorphism significance was investigated by transfection of reporter gene constructs into a H4IIE cell line. Heterozygous GK polymorphisms were identified in 17.9% of SIDS and 20.8% of non-SIDS infants: two rare silent polymorphisms, Y215Y and S263S, in the coding region; a third rare polymorphism, −45G>A, in the hepatic promoter and the most prevalent polymorphism, c.484–29G>C, in a non-coding region upstream from the intron 4–exon 5 junction. A novel heterozygous polymorphism −77G>A in the G6PC1 promoter in 6.3% of non-SIDS and 2.9% of control infants decreased basal G6PC1 promoter activity (p<0.001). We describe three novel polymorphisms in the GK gene, S263S, −45G>A, and a common (14.3%) intronic substitution, c.484–29G>C, in infants who died suddenly and unexpectedly. We identified the first G6PC1 promoter polymorphism, which lowers expression, potentially increasing risk of hypoglycaemia and hence risk of sudden and unexpected death.

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
Fig. 4

Similar content being viewed by others

References

  1. Leach CEA, Blair PS, Fleming PJ, Smith IJ, Platt MW, Berry PJ, Golding J (1999) Epidemiology of SIDS and explained sudden infant deaths. Pediatrics 104:e43

    Article  CAS  PubMed  Google Scholar 

  2. Buck GM, Cookfair DL, Michalek AM, Nasca PC, Standfast SJ, Sever LE, Kramer AA (1989) Intrauterine growth retardation and risk of sudden infant death syndrome (SIDS). Am J Epidemiol 129:874–884

    CAS  PubMed  Google Scholar 

  3. Dwyer T, Ponsonby A-L (1992) Sudden infant death syndrome—insights from epidemiological research. J Epidemiol Community Health 46:98–102

    CAS  PubMed  Google Scholar 

  4. Øyen N, Skjaerven R, Little RE, Wilcox AJ (1995) Fetal growth retardation in sudden infant death syndrome (SIDS) babies and their siblings. Am J Epidemiol 142:84–90

    PubMed  Google Scholar 

  5. Hume R, McGeechan A, Burchell A (1999) Failure to detect preterm infants at risk of hypoglycemia before discharge. J Pediatr 134:499–502

    CAS  PubMed  Google Scholar 

  6. Duvanel CB, Fawer C-L, Cotting J, Hohlfeld P, Matthieu J-M (1999) Long-term effects of neonatal hypoglycaemia on brain growth and psychomotor development in small-for-gestational-age preterm infants. J Pediatr 134:492–498

    CAS  PubMed  Google Scholar 

  7. Emery JL, Howat AJ, Variend S, Vawter GF (1988) Investigation of inborn errors of metabolism in unexpected infant deaths. Lancet 2:29–31

    Article  CAS  PubMed  Google Scholar 

  8. Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Takeda J, Passa P, Stoffel M (1993) Familial hyperglycemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus. N Engl J Med 328:697–702

    Article  CAS  PubMed  Google Scholar 

  9. Gloyn AL (2003) Glucokinase (GCK) mutations in hyper- and hypoglycaemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinaemia of infancy. Human Mutat 22:353–362

    Article  CAS  Google Scholar 

  10. Thomson KL, Gloyn AL, Colclough K, Batten M, Allen LIS, Beards F, Hattersley AT, Ellard S (2003) Identification of 21 novel glucokinase (GCK) mutations in UK and European caucasians with Maturity-onset Diabetes of the Young (MODY). Hum Mutat, Mutation in Brief #657Online

  11. Ellard S, Beards F, Allen LIS, Shepherd M, Ballantyne E, Harvey R, Hattersley AT (2000) A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria. Diabetologia 43:250–253

    Article  CAS  PubMed  Google Scholar 

  12. Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S (1998) Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet 19:268–270

    Article  CAS  PubMed  Google Scholar 

  13. Burchell A, Waddell ID (1991) The molecular basis of the hepatic microsomal glucose-6-phosphatase system. Biochim Biophys Acta 1092:129–137

    Article  CAS  PubMed  Google Scholar 

  14. Arion WJ, Lange AJ, Walls HE, Ballas LM (1980) Evidence for the participation of independent translocases for phosphate and glucose-6-phosphate in the microsomal glucose-6-phosphatase system. J Biol Chem 255:10396–10406

    CAS  PubMed  Google Scholar 

  15. Chen YT, Burchell A (1995) Glycogen storage diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 935–965

    Google Scholar 

  16. Burchell A, Lyall H, Busuttil A, Bell E, Hume R (1992) Glucose metabolism and hypoglycaemia in SIDS. J Clin Pathol 45(suppl 11):39–45

    CAS  PubMed  Google Scholar 

  17. Burchell A, Busuttil A, Bell JE, Hume R (1989) Hepatic microsomal glucose-6-phosphatase system and sudden infant death syndrome. Lancet 2:291–294

    Article  CAS  PubMed  Google Scholar 

  18. Hume R, Burchell A (1993) Abnormal expression of glucose-6-phosphatase in preterm infants. Arch Dis Child 68:202–204

    CAS  PubMed  Google Scholar 

  19. Hume R, McGeechan A, Burchell A (2000) Perinatal factors influencing hepatic glucose-6-phosphatase enzyme activity. J Perinatol 5:301–306

    Article  Google Scholar 

  20. Burchell A, McGeechan A, Hume R (2000) Therapeutic insulin and hepatic glucose-6-phosphatase activity in preterm infants. Arch Dis Child Fetal Neonatal Ed 82:F228–F232

    Article  CAS  PubMed  Google Scholar 

  21. Greengard O, Dewey HK (1967) Initiation by glucagon of the premature development of tyrosine aminotransferase, serine dehydratase, and glucose-6-phosphatase in fetal rat liver. J Biol Chem 242:2986–2991

    CAS  PubMed  Google Scholar 

  22. Docherty K, Clark AR (1993) Transcription of exogenous genes in mammalian cells. In: Hames BD, Higgins SJ (eds) Gene transcription: a practical approach. IRL Press, Oxford, pp 65–121

    Google Scholar 

  23. Ibrahim NM, Marinovic AC, Price SR, Young LG, Frohlich O (2000) Pitfall of an internal control plasmid: response of Renilla luciferase (pRL-TK) plasmid to dihydrotestosterone and dexamethasone. BioTechniques 29:782–784

    CAS  PubMed  Google Scholar 

  24. Pruhova S, Ek J, Lebl J, Sumnik F, Saudek F, Andel M, Pederson O, Hansen T (2003) Genetic epidemiology of MODY in the Czech Republic: new mutations in the MODY genes HNF-4α, GCK and HNF-1α. Diabetologia 46:291–295

    CAS  PubMed  Google Scholar 

  25. Morley R, Brooke OG, Cole TJ, Powell R, Lucas A (1990) Birthweight ratio and outcome in preterm infants. Arch Dis Child 65:30–34

    CAS  PubMed  Google Scholar 

  26. Sawka-Verhelle D, Tartare-Deckert S, Decaux JF, Girard J, Van Obberghen E (2000) Stat 5B, activated by insulin in a Jak-independent fashion, plays a role in glucokinase gene transcription. Endocrinology 141:1977–1988

    Article  CAS  PubMed  Google Scholar 

  27. Schmoll D, Wasner C, Hinds CJ, Allan BB, Walther R, Burchell A (1999) Identification of a cAMP response element within the glucose-6-phosphatase hydrolytic subunit gene promoter which is involved in the transcriptional regulation by cAMP and glucocorticoids in H4IIE hepatoma cells. Biochem J 338:457–463

    Article  CAS  PubMed  Google Scholar 

  28. Lange AJ, Argaud D, El-Maghrabi MR, Pan W, Maitra SR, Pilkis SJ (1994) Isolation of a cDNA for the catalytic subunit of rat liver glucose-6-phosphatase: regulation of gene expression in FAO hepatoma cells by insulin, dexamethasone and cAMP. Biochem Biophys Res Commun 201:302–309

    Article  CAS  PubMed  Google Scholar 

  29. Schmoll D, Allan BB, Burchell A (1996) Cloning and sequencing of the 5’ region of the human glucose-6-phosphatase gene: transcriptional regulation by cAMP, insulin and glucocorticoids in H4IIE hepatoma cells. FEBS Lett 383:63–66

    Article  CAS  PubMed  Google Scholar 

  30. Streeper RS, Svitek CA, Chapman S, Greenbaum LE, Taub R, O’Brien RM (1997) A multicomponent insulin response sequence mediates a strong repression of mouse glucose-6-phosphatase gene transcription by insulin. J Biol Chem 272:11698–11701

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Andrew Cassidy, Molecular Genetics Analysis Facility, University of Dundee for DNA sequencing. This research was funded by Babes in Arms, The Medical Research Council, Tenovus(Scotland), The Scottish Cot Death Trust, The Royal Society, Scottish Executive CSO.

Author information

Authors and Affiliations

  1. Maternal and Child Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK

    Laura Forsyth, Robert Hume & Ann Burchell

  2. Pathology Department, Royal Hospital for Sick Children, Yorkhill NHS Trust, Glasgow, Scotland, UK

    Allan Howatson

  3. Forensic Medicine Unit, University of Edinburgh, Edinburgh, Scotland, UK

    Anthony Busuttil

Authors
  1. Laura Forsyth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Hume
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Allan Howatson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anthony Busuttil
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ann Burchell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ann Burchell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Forsyth, L., Hume, R., Howatson, A. et al. Identification of novel polymorphisms in the glucokinase and glucose-6-phosphatase genes in infants who died suddenly and unexpectedly. J Mol Med 83, 610–618 (2005). https://doi.org/10.1007/s00109-005-0666-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-005-0666-0

Keywords

Search

Navigation