Journal of Endocrinological Investigation

, Volume 33, Issue 11, pp 800–805 | Cite as

The R304X mutation of the aryl hydrocarbon receptor interacting protein gene in familial isolated pituitary adenomas: Mutational hot-spot or founder effect?

  • G. Occhi
  • M. L. Jaffrain-Rea
  • G. Trivellin
  • N. Albiger
  • F. Ceccato
  • E. De Menis
  • M. Angelini
  • S. Ferasin
  • A. Beckers
  • F. Mantero
  • C. Scaroni
Original Articles


Background: Mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene have been described in about 15% of kindreds with familial isolated pituitary adenomas and in a minority of early onset sporadic pituitary adenomas (PA). Among the AIP mutations reported so far, the R304X (AIP R304X) represents, together with the “Finnish mutation” Q14X, the most common one. Methods: Three AIP R304X Italian families, including a newly reported kindred, have been genotyped for 12 genetic markers surrounding the AIP gene in order to look for a potential founder effect in Italy. Disease penetrance and genotype-phenotype correlations were also addressed. Results: Analysis of chromosome 11′ genetic markers revealed a common haplotype in 2 AIP R304X kindreds originating from central Italy. Overall, 17 mutations carriers were identified, including 7 patients and 10 unaffected subjects, respectively, arguing in this case for a disease penetrance of 41%. Mean age at diagnosis was 19.1±6.7 yr old, with females tending to be older than males. Though most PA were somatotropinomas (6/7), a great variability in disease severity was observed, even between subjects sharing the same at-risk haplotype. Conclusion: These data provide strong evidence for a new founder effect of the AIP R304X mutation in central Italy and the observed variations in disease severity point out the role of additional genetic or environmental factors in such kindreds.


AIP FIPA founder effect haplotype analysis pituitary adenoma 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Daly AF, Jaffrain-Rea ML, Ciccarelli A, et al. Clinical characterization of familial isolated pituitary adenomas. J Clin Endocrinol Metab 2006, 91: 3316–23.PubMedCrossRefGoogle Scholar
  2. 2.
    Beckers A, Daly AF. The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol 2007, 157: 371–82.PubMedCrossRefGoogle Scholar
  3. 3.
    Vierimaa O, Georgitsi M, Lehtonen R, et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 2006, 312: 1228–30.PubMedCrossRefGoogle Scholar
  4. 4.
    Aaltonen LA. Aryl hydrocarbon receptor-interacting protein and acromegaly. Horm Res 2007, 68 (Suppl 5): 127–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Daly AF, Vanbellinghen JF, Khoo SK, et al. Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J Clin Endocrinol Metab 2007, 92: 1891–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Georgitsi M, Raitila A, Karhu A, et al. Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptorinteracting protein gene mutations. Proc Natl Acad Sci U S A 2007, 104: 4101–5.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Cazabat L, Libe R, Perlemoine K, et al. Germ line-inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas. Eur J Endocrinol 2007, 157: 1–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Barlier A, Vanbellinghen JF, Daly AF, et al. Mutations in the aryl hydrocarbon receptor interacting protein gene are not highly prevalent among subjects with sporadic pituitary adenomas. J Clin Endocrinol Metab 2007, 92: 1952–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Georgitsi M, De Menis E, Cannavò S, et al. Aryl hydrocarbon receptor interacting protein (AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas. Clin Endocrinol (Oxf) 2008, 69: 621–7.CrossRefGoogle Scholar
  10. 10.
    Leontiou CA, Gueorguiev M, van der Spuy J, et al. The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J Clin Endocrinol Metab 2008, 93: 2390–401.PubMedCrossRefGoogle Scholar
  11. 11.
    Scaroni C, Selice R, Benedini S, et al. Adrenal morpho-functional alterations in patients with acromegaly. J Endocrinol Invest 2008, 31: 602–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Grottoli S, Razzore P, Gaia D, et al. Three-hour spontaneous GH secretion profile is as reliable as oral glucose tolerance test for the diagnosis of acromegaly. J Endocrinol Invest 2003, 26: 123–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Ferretti E, Jaffrain Rea ML, Asteria C, et al. Two familial giant pituitary adenomas associated with overweight: clinical, morphological and genetic features. Eur J Endocrinol 2001, 144: 227–35.PubMedCrossRefGoogle Scholar
  14. 14.
    De Menis E, PrezantTR. Isolated familial somatotropinomas: clinical features and analysis of the MEN1 gene. Pituitary 2002, 5: 11–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Naves LA, Daly AF, Vanbellinghen JF, et al. Variable pathological and clinical features of a large Brazilian family harboring a mutation in the aryl hydrocarbon receptor-interacting protein gene. Eur J Endocrinol 2007, 157: 383–91.PubMedCrossRefGoogle Scholar
  16. 16.
    Daly AF, Tichomirow MA, Beckers A. Update on familial pituitary tumors: from multiple endocrine neoplasia type 1 to familial isolated pituitary adenoma. Horm Res 2009, 71 (Suppl. 1): 105–11.Google Scholar
  17. 17.
    Bell DR, Poland A. Binding of aryl hydrocarbon receptor (AhR) to AhR-interacting protein. The role of hsp90. J Biol Chem 2000, 275: 36407–14.PubMedCrossRefGoogle Scholar
  18. 18.
    Petrulis JR, Perdew GH. The role of chaperone proteins in the aryl hydrocarbon receptor core complex. Chem Biol Interact 2002, 141: 25–40.PubMedCrossRefGoogle Scholar
  19. 19.
    Jaffrain-Rea ML, Angelini M, Gargano D, et al. Expression of aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor interacting protein (AIP) in pituitary adenomas: pathological and clinical implications. Endocr Relat Cancer 2009, 16: 1029–43.PubMedCrossRefGoogle Scholar
  20. 20.
    Peltonen L Molecu lar background of the Finnish disease heritage. Ann Med 1997, 29: 553–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Vargiolu M, Fusco D, Kurelac I, et al. The tyrosine kinase receptor RET interacts in vivo with AIP to alter survivin availability. J Clin Endocrinol Metab 2009, 94: 2571–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Krawczak M, Ball EV, Cooper DN. Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes. Am J Hum Genet 1998, 63: 474–88.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Jennings J, Georgitsi M, Holdaway I, et al. Aggressive pituitary adenomas occurring in young patients in a large Polynesian kindred with a germline R271W mutation in the AIP gene. Eur J Endocrinol 2009, 161: 799–804.PubMedCrossRefGoogle Scholar
  24. 24.
    Georgitsi M, Heliövaara E, Paschke R, et al. Large genomic deletions in AIP in pituitary adenoma predisposition. J Clin Endocrinol Metab 2008, 93: 4146–51.PubMedCrossRefGoogle Scholar
  25. 25.
    Cazabat L, Guillaud-Bataille M, Bertherat J, Raffin-Sanson ML. Mutations of the gene for the aryl hydrocarbon receptor-interacting protein in pituitary adenomas. Horm Res 2009, 71: 132–41.PubMedCrossRefGoogle Scholar
  26. 26.
    Khoo SK, Pendek R, Nickolov R, et al. Genome-wide scan identifies novel modifier loci of acromegalic phenotypes for isolated familial somatotropinoma. Endocr Relat Cancer 2009, 16: 1057–63.PubMedCrossRefGoogle Scholar
  27. 27.
    Jaffrain-Rea ML, Tichomirowa M, Daly AF, Beckers A. Pituitary adenomas in young patients: when should we consider a genetic predisposition? Expert Rev Endocrinol Metab 2010, 4: 529.CrossRefGoogle Scholar
  28. 28.
    Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001, 86: 5658–71.PubMedCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2010

Authors and Affiliations

  • G. Occhi
    • 1
  • M. L. Jaffrain-Rea
    • 2
    • 3
  • G. Trivellin
    • 1
  • N. Albiger
    • 1
  • F. Ceccato
    • 1
  • E. De Menis
    • 4
  • M. Angelini
    • 2
  • S. Ferasin
    • 1
  • A. Beckers
    • 5
  • F. Mantero
    • 1
  • C. Scaroni
    • 1
  1. 1.Endocrinology Division, Department of Medical and Surgical SciencesPadua Hospital/UniversityPadua
  2. 2.Department of Experimental MedicineUniversity of L’AquilaL’Aquila
  3. 3.Neuromed Institute IRCCSPozzilli
  4. 4.Department of Internal MedicineGeneral HospitalMontebelluna (Treviso)Italy
  5. 5.Endocrinology, Centre Hospitalier Universitaire de LiègeUniversity of LiègeLiègeBelgium

Personalised recommendations