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Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion.

ABSTRACT: BACKGROUND:Aryl hydrocarbon receptor-interacting protein (AIP) is evolutionarily conserved and expressed widely throughout the organism. Loss-of-function AIP mutations predispose to young-onset pituitary adenomas. AIP co-localizes with growth hormone in normal and tumorous somatotroph secretory vesicles. AIP protein is detectable in circulation. We aimed to investigate possible AIP and GH co-secretion, through studying serum AIP and GH levels at baseline and after GH stimulation or suppression, in GH deficiency (GHD) and in acromegaly patients. SUBJECTS AND METHODS:Insulin tolerance test (ITT) was performed in GHD patients (n=13) and age-BMI-matched normal GH axis control patients (n=31). Oral glucose tolerance test (OGTT) was performed in active acromegaly patients (n=26) and age-BMI-matched normal GH axis control patients (n=18). In-house immunometric assay was developed for measuring circulating AIP. RESULTS:Serum AIP levels were in the 0.1ng/ml range independently of gender, age or BMI. Baseline AIP did not differ between GHD and non-GHD or between acromegaly and patients with no acromegaly. There was no change in peak, trough or area under the curve during OGTT or ITT. Serum AIP did not correlate with GH during ITT or OGTT. CONCLUSIONS:Human circulating serum AIP in vivo was assessed by a novel immunometric assay. AIP levels were independent of age, sex or BMI, and unaffected by hypoglycaemia or hyperglycaemia. Despite co-localization in secretory vesicles, AIP and GH did not correlate at baseline or during GH stimulation or suppression tests. A platform of reliable serum AIP measurement is established for further research of its circulatory source, role and impact.

SUBMITTER: Stojanovic M

PROVIDER: S-EPMC6432870 | biostudies-other | 2019 Mar

REPOSITORIES: biostudies-other

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Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion.

Stojanovic Marko M Wu Zida Z Stiles Craig E CE Miljic Dragana D Soldatovic Ivan I Pekic Sandra S Doknic Mirjana M Petakov Milan M Popovic Vera V Strasburger Christian C Korbonits Márta M

Endocrine connections 20190401 4

<h4>Background</h4>Aryl hydrocarbon receptor-interacting protein (AIP) is evolutionarily conserved and expressed widely throughout the organism. Loss-of-function AIP mutations predispose to young-onset pituitary adenomas. AIP co-localizes with growth hormone in normal and tumorous somatotroph secretory vesicles. AIP protein is detectable in circulation. We aimed to investigate possible AIP and GH co-secretion, by studying serum AIP and GH levels at baseline and after GH stimulation or suppressio ...[more]

PMID: 30830858

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Project description:Objective/purposeThe aryl hydrocarbon receptor (AHR) pathway plays a critical role in the biology of Growth Hormone (GH)-secreting pituitary tumor (somatotropinoma). Germline rs2066853 AHR variant was found to be more frequent among acromegaly patients and associated with a more severe disease with larger invasive somatropinoma, and with resistance to somatostatin analogs treatment in patients living in polluted areas. However, no somatic changes in AHR gene have been reported so far in acromegaly patients. On that basis, the aim of the study was to assess at the somatic level the AHR gene status encompassing exon 10 region, also because of the high rate of variants found in this genomic region.MethodsA cohort of 13 patients aged 20-76 years with biochemical, clinical and histological diagnosis of somatotropinoma was studied. DNA and RNA from pituitary tumor histological samples have been extracted and analyzed by PCR and direct sequencing for AHR gene variants, and compared with corresponding patients' germline DNA as well as normal pituitary tissue as reference control.ResultsA degenerated letter codes in the region corresponding to AHR exon 10 (c.1239-c.2056) was detected in somatotropinomas-derived DNA but not in that of matched germline and pituitary normal tissue. By multiple PCR and sequencing analysis, we observed amplification only before codon 1246 and after codon 1254, confirming the presence of a tumor-restricted somatic deletion in the 5' upstream region of AHR exon 10. Analysis of PCR-amplified cDNA revealed a wildtype sequence of exon 9 and 10 in normal pituitary tissue, and a wildtype sequence of exon 9 and 10 up to codon 1246 and no sequence after the deletion region (c.1246-c.1254) in 6 out of 9 tumor samples. Patients carrying the germline rs2066853 AHR variant showed no somatic LOH at the corresponding genetic locus.ConclusionThis is the first demonstration of a recurrent somatic deletion in the exon 10 of the AHR gene in somatotropinomas. The functional impact of this genetic finding needs to be clarified.

Dataset Information

Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion.

Publications

Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion.

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