Skip to main content
SpringerLink
Log in

Elevated placental expression of the imprinted PHLDA2 gene is associated with low birth weight

Journal of Molecular Medicine Aims and scope Submit manuscript

Cite this article

Abstract

The identification of genes that regulate fetal growth will help establish the reasons for intrauterine growth restriction. Most autosomal genes are expressed biallelically, but some are imprinted, expressed only from one parental allele. Imprinted genes are associated with fetal growth and development. The growth of the fetus in utero relies on effective nutrient transfer from the mother to the fetus via the placenta. Some current research on the genetic control of fetal growth has focused on genes that display imprinted expression in utero. The expression levels of four imprinted genes, the paternally expressed insulin growth factor 2 (IGF2), the mesoderm-specific transcript isoform 1 (MEST); the maternally expressed pleckstrin homology-like domain, family A, member 2 (PHLDA2); and the polymorphically imprinted insulin-like growth factor 2 (IGF2R) gene are all known to have roles in fetal growth and were studied in the placentae of 200 white European, normal term babies. The quantitative expression analysis with real-time PCR showed the maternally expressing PHLDA2 but not the paternally expressing IGF2 and MEST, nor the polymorphic maternally expressing IGF2R placental levels to have a statistically significant effect on birth weight. PHLDA2 expression levels are negatively correlated with size at birth. These data implicate PHLDA2 as an imprinted gene important in fetal growth and also as a potential marker of fetal growth.

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

References

  1. Moore T, Haig D (1991) Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet 7:45–49

    PubMed  CAS  Google Scholar 

  2. Abu-Amero SN, Monk D, Apostolidou S, Stanier P, Moore GE (2006) Imprinted genes and their role in human fetal growth. Cytogenet Genome Res 113:262–270

    Article  PubMed  CAS  Google Scholar 

  3. DeChiara TM, Efstratiadis A, Robertson EJ (1990) A growth deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 345:78–80

    Article  PubMed  CAS  Google Scholar 

  4. Giannoukakis N, Deal C, Paquette J, Goodyer CG, Polychronakos C (1993) Parental genomic imprinting of the human IGF2 gene. Nat Genet 4:98–101

    Article  PubMed  CAS  Google Scholar 

  5. Brice AL, Cheetham JE, Bolton VN, Hill NC, Schofield PN (1989) Temporal changes in the expression of the insulin-like growth factor II gene associated with tissue maturation in the human fetus. Development 106:543–554

    PubMed  CAS  Google Scholar 

  6. Constancia M, Hemberger M, Hughs J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C, Wolf R (2002) Placental specific IGF-II is a major modulator of placental and fetal growth. Nature 417:945–948

    Article  PubMed  CAS  Google Scholar 

  7. Scott CD, Weiss J (2000) Soluble insulin-like growth factor II/mannose 6-phosphate receptor inhibits DNA synthesis in insulin-like growth factor II sensitive cells. J Cell Physiol 182:62–68

    Article  PubMed  CAS  Google Scholar 

  8. Monk D, Arnaud P, Apostolidou S, Hills FA, Kelsey G, Stanier P, Feil R, Moore GE (2006) Limited evolutionary conservation of imprinting in the human placenta. PNAS 103(17):6623–6628

    Article  PubMed  CAS  Google Scholar 

  9. Lau MM, Stewart CE, Liu Z, Bhatt H, Rotwein P, Stewart CL (1994) Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. Genes Dev 8:2953–2963

    PubMed  CAS  Google Scholar 

  10. Jirtle RL (1999) Genomic imprinting and cancer. Exp Cell Res 248:18–24

    Article  PubMed  CAS  Google Scholar 

  11. Salas M, John R, Saxena A, Barton S, Frank D, Fitzpatrick G, Higgins MJ, Tycko B (2004) Placental growth retardation due to loss of imprinting of Phlda2. Mech Dev 121:1199–1210

    Article  PubMed  CAS  Google Scholar 

  12. Onyango P, Miller W, Lehoczky J, Leubg CT, Birren B, Wheelan S, Dewar K, Feinberg AP (2000) Sequence and comparative analysis of the mouse 1-megabase region orthologous to human 11p15 imprinted domain. Genome Res 10:1697–1710

    Article  PubMed  CAS  Google Scholar 

  13. Park CG, Lee SY, Kandala G, Lee SY, Choi Y (1996) A novel gene product that couples TCR signalling to Fas (CD95) expression in activation-induced cell death. Immunity 4:583–591

    Article  PubMed  CAS  Google Scholar 

  14. Saxena A, Frank D, Panichkul P, Van den Veyver IB, Tycko B, Thaker H (2003) The product of the imprinted IPL marks human villous cytotrophoblast and is lost in complete hydatidiform mole. Placenta 24:835–842

    Article  PubMed  CAS  Google Scholar 

  15. Scwienbacher C, Angioni A, Scelfo R, Veronese A, Calin GA, Massazza G, Hatada I, Barbanti-Brodano G, Negrini M (2000) Abnormal RNA expression of 11p15 imprinted genes and kidney developmental genes in Wilms’ tumour. Cancer Res 60:1521–1525

    Google Scholar 

  16. McMinn J, Wei M, Schupf N, Cusmai J, Johnson EB, Smith AC, Weksberg R, Thaker HM, Tycko B (2006a) Unbalanced placental expression of imprinted genes in human intrauterine growth restriction. Placenta 27:540–549

    Article  PubMed  CAS  Google Scholar 

  17. Lefebvre L, Viville S, Barton SC, Ishino F, Keverne EB, Surani MA (1998) Abnormal maternal behaviour and growth retardation associated with loss of the imprinted gene Mest. Nat Genet 20:163–169

    Article  PubMed  CAS  Google Scholar 

  18. Kobayashi S, Uemura H, Kohda T, Nagai T, Chinen Y, Naritomi K, Kinoshita EI, Ohashi H, Imaizumi K, Tsukahara M, Sugio Y, Tonoki H, Kishino T, Tanaka T, Yamada M, Tsutsumi O, Niikawa N, Kaneko-Ishino T, Ishino F (2001) No evidence of PEG1/MEST gene mutations in Silver–Russell syndrome patients. Am J Med Genet 104:225–231

    Article  PubMed  CAS  Google Scholar 

  19. Kosaki K, Kosaki R, Craigen WJ, Matsuo N (2000) Isoform-specific imprinting of the human PEG1/MEST gene. Am J Hum Genet 66(1):309–312

    Article  PubMed  CAS  Google Scholar 

  20. Pedersen IS, Dervan P, McGoldrick A, Harrison M, Ponchel F, Speirs V, Isaacs JD, Gorey T, McCann A (2002) Promoter switch: a novel mechanism causing biallelic PEG1/MEST expression in invasive breast cancer. Hum Mol Genet 11:1449–1453

    Article  PubMed  CAS  Google Scholar 

  21. Harrell FE (2001) Regression modelling strategies: with applications to linear models, logistic regression, and survival analysis. In: Harrell FE (ed) Springer, Berlin Heidelberg New York, pp 16–26

  22. Hitchins MP, Moore GE (2004) Genomic imprinting in fetal growth and development. Reprod Med Rev 11:1–24

    Article  CAS  Google Scholar 

  23. Eggenschwiler J, Ludwig T, Fisher P, Leighton PA, Tilghman SM, Efstratiadis A (1997) Mouse mutant embryos over-expressing IGF-II exhibit phenotypic features of the Beckwith–Wiedemann and Simpson–Golabi–Behmel syndromes. Genes Dev 11:3128–3142

    PubMed  CAS  Google Scholar 

  24. Takahashi K, Kobayashi T, Kanayama N (2000) p57(Kip2) regulates the proper development of labyrinthine and spongiotrophoblasts. Mol Hum Reprod 6:1019–1025

    Article  PubMed  CAS  Google Scholar 

  25. Frank D, Fortino W, Clark L, Musalo R, Wang W, Saxena A, Li CM, Reik W, Ludwig T, Tycko B (2002) Placenta overgrowth in mice lacking the imprinting gene lpl. PNAS 99:7490–7495

    Article  PubMed  CAS  Google Scholar 

  26. Lo HC, Tsao LY, Hsu WY, Chen HN, Yu WK, Chi CY (2002) Relation of cord serum levels of growth hormone, insulin-like growth factors, insulin-like growth factor binding proteins, leptin, and interleukin-6 with birth weight, birth length and head circumference in term and preterm neonates. Nutrition 18:604–608

    Article  PubMed  CAS  Google Scholar 

  27. Klauwer D, Blum WF, Hanitsch S, Rascher W, Lee PD, Kiess W (1997) IGF-I, IGF-II, free IGF-I and IGFBP-1, -2 and -3 levels in venous cord blood: relationship to birth weight, length and gestational age in healthy newborns. Acta Paediatr 86:826–833

    Article  PubMed  CAS  Google Scholar 

  28. Ong K, Kratzsch J, Kiess W, Team ALSPAC Study, Costello M, Scott C, Dunger D (2000) Size at birth and cord blood levels of insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/mannose-6-phosphate receptor in term human infants. J Clin Endocrinol Metab 85:4266–4269

    Article  PubMed  CAS  Google Scholar 

  29. Sibley CP, Coan PM, Ferguson-Smith AC, Dean W, Hughes J, Smith P, Reik W, Burton GJ, Fowden AL, Constância M (2004) Placental-specific insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta. PNAS 101:8204–8208

    Article  PubMed  CAS  Google Scholar 

  30. Monk D, Sanches R, Arnaud P, Apostolidou S, Hills FA, Abu-Amero S, Murrell A, Friess H, Reik W, Stanier P, Constancia M, Moore GE (2006) Imprinting of IGF2 P0 transcript and novel alternatively spliced INS-IGF2 isoforms show differences between mouse and human. Hum Mol Genet 15(8):1259–1269

    Article  PubMed  CAS  Google Scholar 

  31. Piras G, El Kharroubi A, Kozlov S, Escalante-Alcalde D, Hernandez L, Copeland NG, Gilbert DJ, Jenkins NA, Stewart CL (2000) Zac1 (Lot1), a potential tumour suppressor gene and the gene for epsilon-sarcoglycan are maternally imprinted genes: identification by a subtractive screen of novel uniparental fibroblast lines. Mol Cell Biol 9:3308–3315

    Article  Google Scholar 

  32. McMinn J, Wei M, Sadovsky Y, Thaker HM, Tycko B (2006b) Imprinting of PEG1/MEST isoform 2 in human placenta. Placenta 27:119–126

    Article  PubMed  CAS  Google Scholar 

  33. Shi W, Lefebvre L, Yu Y, Otto S, Krella A, Orth A, Fundele R (2004) Loss-of-imprinting of Peg1 in mouse interspecies hybrids is correlated with altered growth. Genesis 39:65–72

    Article  PubMed  CAS  Google Scholar 

  34. Kalscheuer VM, Mariman EC, Schepens MT, Rehder H, Ropers HH (1993) The insulin-like growth factor type-2 receptor gene is imprinted in the mouse but not in humans. Nat Genet 5(1):74–78

    Article  PubMed  CAS  Google Scholar 

  35. Riesewijk AM, Xu YQ, Schepens MT, Mariman EM, Polychronakos C, Ropers HH, Kalscheuer VM (1998) Absence of an obvious molecular imprinting mechanism in a human fetus with monoallelic IGF2R expression. Biochem Biophys Res Commun 245:272–277

    Article  PubMed  CAS  Google Scholar 

  36. Nishiwaki K, Niikawa N, Ishikawa M (1997) Polymorphic and tissue-specific imprinting of the human Wilms tumor gene, WT1. J Hum Genet 42:205–211

    CAS  Google Scholar 

Download references

Acknowledgement

We thank the families who participated in the study and the phlebotomists and midwives of Queen Charlotte’s Hospital for their co-operation. This work was supported by WellBeing and the Dunhill Medical Trust.

Author information

Authors and Affiliations

  1. Translational Research Laboratory, Department of Gynaecological Oncology, The Windeyer Institute of Medical Sciences, 46 Cleveland Street, London, W1T 4JF, UK

    S. Apostolidou

  2. Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK

    S. Abu-Amero, J. Frost, P. Stanier & G. E. Moore

  3. Institute of Developmental and Reproductive Biology, Division of Paediatrics, Obstetrics and Gynaecology, Imperial College London, Hammersmith Campus, London, W12 0NN, UK

    K. O’Donoghue, O. Olafsdottir & K. M. Chavele

  4. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK

    J. C. Whittaker

  5. Academic Division of Obstetrics and Gynaecology, City Hospital, Nottingham, NG5 1PB, UK

    P. Loughna

Authors
  1. S. Apostolidou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Abu-Amero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. O’Donoghue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Frost
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O. Olafsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. M. Chavele
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. C. Whittaker
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P. Loughna
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P. Stanier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G. E. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Apostolidou.

Additional information

S. Apostolidou and S. Abu-Amero contributed equally to the research.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Apostolidou, S., Abu-Amero, S., O’Donoghue, K. et al. Elevated placental expression of the imprinted PHLDA2 gene is associated with low birth weight. J Mol Med 85, 379–387 (2007). https://doi.org/10.1007/s00109-006-0131-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-006-0131-8

Keywords

search

Navigation