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J Endocrinol Invest. 2010 Dec;33(11):800-5. doi: 10.3275/6956. Epub 2010 Mar 30.

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

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Endocrinology Division, Department of Medical and Surgical Sciences, Padua Hospital/University, Via Ospedale 105, Padua, Italy.



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 (AIPR304X) represents, together with the "Finnish mutation" Q14X, the most common one.


Three AIPR304X 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.


Analysis of chromosome 11' genetic markers revealed a common haplotype in 2 AIPR304X 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.


These data provide strong evidence for a new founder effect of the AIPR304X mutation in central Italy and the observed variations in disease severity point out the role of additional genetic or environmental factors in such kindreds.

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