Skip to main content
SpringerLink
Log in

A novel recessive splicing mutation in the POU1F1 gene causing combined pituitary hormone deficiency

  • Original Articles
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Background: Mutations in the gene encoding the pituitary transcription factor POU1F1 (Pit-1, pituitary transcription factor-1) have been described in combined pituitary hormone deficiency (CPHD). Aim: The aim of this study was the characterisation of the molecular defect causing CPHD in a patient born to consanguineous parents. Subject and methods: The case of a 12.5-yr-old girl presenting with severe growth failure at diagnosis (−3 SD score at 3 months) and deficiency of GH, PRL, and TSH was investigated for the presence of POU1F1 gene mutations by denaturing high performance liquid chromatography analysis. Results: A novel mutation adjacent to the IVS2 splicing acceptor site (IVS2-3insA) was identified in the patient at the homozygous state. Analysis of patient’s lymphocyte mRNA and an in vitro splicing assay revealed the presence of 2 aberrant splicing products: a) deletion of the first 71 nucleotides of exon 3, altering the open reading frame and generating a premature stop codon, b) total exon 3 skipping resulting in an in frame deleted mRNA encoding a putative protein lacking part of the transactivation domain and of the POU-specific homeodomain. Notably, the patient’s relatives heterozygous for the mutation had PRL levels under the normal range with no evident clinical symptoms. Conclusions: The IVS2-3insA mutation, responsible for CPHD at the homozygous state, causes the presence of 2 aberrant splicing products encoding non-functional products. In the heterozygotes one normal allele might not guarantee a complete pituitary function.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Theill LE, Karin M. Transcriptional control of GH expression and anterior pituitary development. Endocr Rev 1993, 14: 670–89.

    PubMed  CAS  Google Scholar 

  2. Cohen LE, Wondisford FE, Radovick S. Role of Pit-1 in the gene expression of growth hormone, prolactin, and thyrotropin. Endocrinol Metab Clin North Am 1996, 25: 523–40.

    Article  PubMed  CAS  Google Scholar 

  3. Ingraham HA, Flynn SE, Voss JW, et al. The POU-specific domain of Pit-1 is essential for sequence-specific, high affinity DNA binding and DNA-dependent Pit-1-Pit-1 interactions. Cell 1990, 61: 1021–33.

    Article  PubMed  CAS  Google Scholar 

  4. Bodner M, Karin M. A pituitary-specific trans-acting factor can stimulate transcription from the growth hormone promoter in extracts of nonexpressing cells. Cell 1987, 50: 267–75.

    Article  PubMed  CAS  Google Scholar 

  5. Mangalam HJ, Albert VR, Ingraham HA et al. A pituitary POU domain protein, Pit-1, activates both growth hormone and prolactin promoters transcriptionally. Genes Dev 1989, 3: 946–58.

    Article  PubMed  CAS  Google Scholar 

  6. Petersenn S, Rasch AC, Heyens M, Schulte HM. Structure and regulation of the human growth hormone-releasing hormone receptor gene. Mol Endocrinol 1998, 12: 233–47.

    Article  PubMed  CAS  Google Scholar 

  7. Chen RP, Ingraham HA, Treacy MN, Albert VR, Wilson L, Rosenfeld MG. Autoregulation of Pit-1 gene expression mediated by two cisactive promoter elements. Nature 1990, 346: 583–6.

    Article  PubMed  CAS  Google Scholar 

  8. Kievit P, Maurer RA. The pituitary-specific transcription factor, Pit-1, can direct changes in the chromatin structure of the prolactin promoter. Mol Endocrinol 2005, 19: 138–47.

    Article  PubMed  CAS  Google Scholar 

  9. Xu L, Lavinsky RM, Dasen JS, et al. Signal-specific co-activator domain requirements for Pit-1 activation. Nature 1998, 395: 301–6.

    Article  PubMed  CAS  Google Scholar 

  10. Tatsumi K, Miyai K, Notomi T, et al. Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nat Genet 1992, 1: 56–8.

    Article  PubMed  CAS  Google Scholar 

  11. Radovick S, Nations M, Du Y, Berg LA, Weintraub BD, Wondisford FE. A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency. Science 1992, 257: 1115–8.

    Article  PubMed  CAS  Google Scholar 

  12. Pfäffle RW, DiMattia GE, Parks JS, et al. Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 1992, 257: 1118–21.

    Article  PubMed  Google Scholar 

  13. Cohen LE, Zanger K, Brue T, Wondisford FE, Radovick S. Defective retinoicacid regulation of the Pit-1 gene enhancer: a novel mechanism of combined pituitary hormone deficiency. Mol Endocrinol 1999, 13: 476–4.

    Article  PubMed  CAS  Google Scholar 

  14. Pernasetti F, Milner RD, al Ashwal AA, et al. Pro239Ser: a novel recessive mutation of the Pit-1 gene in seven Middle Eastern children with growth hormone, prolactin, and thyrotropin deficiency. J Clin Endocrinol Metab 1998, 83: 2079–83.

    PubMed  CAS  Google Scholar 

  15. Pellegrini-Bouiller I, Bélicar P, Barlier A, et al. A new mutation of the gene encoding the transcription factor Pit-1 is responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab 1996, 81: 2790–6.

    PubMed  CAS  Google Scholar 

  16. Brown MR, Parks JS, Adess ME, et al. Central hypothyroidism reveals compound heterozygous mutations in the Pit-1 gene. Horm Res 1998, 49: 98–102.

    Article  PubMed  CAS  Google Scholar 

  17. Irie Y, Tatsumi K, Ogawa M, et al. A novel E250X mutation of the PIT-1 gene in a patient with combined pituitary hormone deficiency. Endocr J 1995, 42: 351–4.

    Article  PubMed  CAS  Google Scholar 

  18. Hendriks-Stegeman BI, Augustijn KD, Bakker B, Holthuizen P, van der Vliet PC, Jansen M. Combined pituitary hormone deficiency caused by compound heterozygosity for two novel mutations in the POU domain of the Pit1/POU1 F1 gene. J Clin Endocrinol Metab 2001, 86: 1545–50.

    PubMed  CAS  Google Scholar 

  19. Gat-Yablonski G, Lazar L, Pertzelan A, Phillip M. A novel mutation in PIT-1: phenotypic variability in familial combined pituitary hormone deficiencies. J Pediatr Endocrinol Metab 2002, 15: 325–30.

    Article  PubMed  CAS  Google Scholar 

  20. Fofanova OV, Takamura N, Kinoshita E et al. Rarity of PIT1 involvement in children from Russia with combined pituitary hormone deficiency. Am J Med Genet 1998, 77: 360–5.

    Article  PubMed  CAS  Google Scholar 

  21. Ohta K, Nobukuni Y, Mitsubuchi H et al. Mutations in the Pit-1 gene in children with combined pituitary hormone deficiency. Biochem Biophys Res Commun 1992, 189: 851–5.

    Article  PubMed  CAS  Google Scholar 

  22. Parks JS, Abdul-Latif H, Kinoshita E, Meacham LR, Pfäffle RW, Brown MR. Genetics of growth hormone gene expression. Horm Res 1993, 40: 54–61.

    Article  PubMed  CAS  Google Scholar 

  23. Blankenstein O, Mühlenberg R, Kim C, Wüller S, Pfäffle RW, Heimann G. A new C-terminal located mutation (V272ter) in the PIT-1 gene manifesting with severe congenital hypothyroidism. Possible functionality of the PIT-1 C-terminus. Horm Res 2002, 56: 81–6.

    Article  Google Scholar 

  24. McLennan K, Jeske Y, Cotterill A, et al. Combined pituitary hormone deficiency in Australian children: clinical and genetic correlates. Clin Endocrinol (Oxf) 2003, 58: 785–94

    Article  CAS  Google Scholar 

  25. Malvagia S, Poggi GM, Pasquini E, et al. The de novo Q167K mutation in the POU1 F1 gene leads to combined pituitary hormone deficiency in an Italian patient. Pediatr Res 2003, 54: 635–40.

    Article  PubMed  CAS  Google Scholar 

  26. Hashimoto Y, Cisternino M, Cohen LE. A novel nonsense mutation in the Pit-1 gene: evidence for a gene dosage effect. J Clin Endocrinol Metab 2003, 88: 1241–7.

    Article  PubMed  CAS  Google Scholar 

  27. Turton JP, Reynaud R, Mehta A, et al. Novel mutations within the POU1 F1 gene associated with variable combined pituitary hormone deficiency. J Clin Endocrinol Metab 2005, 90: 4762–70.

    Article  PubMed  CAS  Google Scholar 

  28. Snabboon T, Plengpanich W, Buranasupkajorn P, et al. A novel germline mutation, IVS4+1G>A, of the POU1 F1 gene underlying combined pituitary hormone deficiency. Horm Res 2008, 69: 60–4.

    Article  PubMed  CAS  Google Scholar 

  29. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 1976, 51: 170–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. D’Alfonso S, Mellai M, Giordano M, et al; Italian Group for the Study of Multiple Sclerosis Genetics. Identification of single nucleotide variations in the coding and regulatory regions of the myelin-associated glycoprotein gene and study of their association with multiple sclerosis. J Neuroimmunol 2002, 126: 196–204.

    Article  PubMed  Google Scholar 

  31. Li S, Crenshaw EB 3rd, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene Pit-1. Nature 1990, 347: 528–33.

    Article  PubMed  CAS  Google Scholar 

  32. Frisch H, Kim C, Häusler G, Pfäffle R. Combined pituitary hormone deficiency and pituitary hypoplasia due to a mutation of the Pit-1 gene. Clin Endocrinol (Oxf) 2000, 52: 661–5.

    Article  CAS  Google Scholar 

  33. Shyu AB, Wilkinson MF, van Hoof A. Messenger RNA regulation: to translate or to degrade. EMBO J 2008, 27: 471–81.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  34. Demarco IA, Voss TC, Booker CF, Day RN. Dynamic interactions between Pit-1 and C/EBPalpha in the pituitary cell nucleus. Mol Cell Biol 2006, 26: 8087–98.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Douchi T, Nakae M, Yamamoto S, Iwamoto I, Oki T, Nagata Y. A woman with isolated prolactin deficiency. Acta Obstet Gynecol Scand 2001, 80: 368–70.

    PubMed  CAS  Google Scholar 

  36. Saito T, Tojo K, Oki Y, et al. A case of prolactin deficiency with familial puerperal alactogenesis accompanying impaired ACTH secretion. Endocr J 2007, 54: 59–62.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Human Genetics, Department of Medical Sciences, Eastern Piedmont University and Interdisciplinary Research Center on Autoimmune Diseases, Novara, Italy

    Y. Carlomagno, M. Godi, S. Mellone, L. Tiradani, P. Momigliano-Richiardi & M. Giordano

  2. Department of Pediatrics, University of Naples “Federico II”, Naples, Italy

    M. Salerno & D. Capalbo

  3. Unit of Pediatrics, Department of Medical Sciences, Eastern Piedmont University, Novara, Italy

    D. Vivenza, G. Corneli & G. Bona

Authors
  1. Y. Carlomagno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Salerno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Vivenza
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. Capalbo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Godi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Mellone
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L. Tiradani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G. Corneli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P. Momigliano-Richiardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G. Bona
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M. Giordano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Giordano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carlomagno, Y., Salerno, M., Vivenza, D. et al. A novel recessive splicing mutation in the POU1F1 gene causing combined pituitary hormone deficiency. J Endocrinol Invest 32, 653–658 (2009). https://doi.org/10.1007/BF03345736

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03345736

Keywords

Search

Navigation