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

Abstract

ABSTRACT. 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. (J. Endocrinol. Invest. 33: 800-805, 2010)

Screening for AIP gene mutations in a Han Chinese pituitary adenoma cohort followed by LOH analysis

“…However, most identified PA patients harboring p.Q14* (18/19) come from a limited geographical region in Northern Finland, while only one patient comes from Estonia, a neighboring country east of Finland (7,25). Haplotype analyses by Occhi et al (38) and Chahal et al (33) provided evidence of a founder effect for p.R304* in central Italy and in Northern Ireland respectively. Cazabat et al (39) also detected the mutation in a child with SPA from France, and in the reply to their letter, Stals reported their further haplotype analysis of patients with R304* mutations from several countries, indicating that the mutation can occur independently in various areas of the world and also have a founder effect in some cases.…”

Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis

“…Markers were PCR amplified from genomic DNA, separated on an ABI 3730XL DNA sequencer, and analyzed with Peak Scanner v1.0 software (Applied Biosystems). Genetic markers' primers sequences and amplification condition were reported elsewhere (16).…”

Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations

“…Direct AIP sequencing was performed on leukocyte DNA as previously reported , Occhi et al 2010. A search for activating mutations of the GNAS1 gene at codons 201 and 227 (Gsp) was performed on tumour DNA at each centre, as described previously (Barlier et al 1998, Lania et al 1998, Occhi et al 2011, primers and conditions for GNAS1 sequencing in the leading centre being available on demand.…”