Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene Mutations in Acromegaly (AIP)

July 18, 2013 updated by: ZULEYHA KARACA, TC Erciyes University

Investigation of Prevalence and Clinical Effects of Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene Mutations With DNA Sequence Analysis in Acromegaly Patients in Turkey

Acromegaly is a rare disease caused by growth hormone (GH) secreting pituitary adenoma in more than 95% of cases. Acromegaly can be seen sporadically or may be associated with a variety of genetic syndromes such as Multiple Endocrine Neoplasia Type 1, Carney Complex, familial isolated pituitary adenoma (FIPA) and Mc-Cune Albright Syndrome. The accompanying features of these syndromes and family history are helpful in the differential diagnosis. Aryl hydrocarbon receptor (AHR)-interacting protein (AIP) gene mutations can be seen sporadically as well as in FIPA. But the prescience of the presence of AIP mutation is limited by positive family history and early-onset of acromegaly. Furthermore, the probability of the patient to be the index case of the family should not be ignored.

Screening for AIP gene mutation is recommended in patients with pituitary adenomas of childhood-onset, GH or prolactin secreting tumors who are diagnosed before the age of 30 years and positive family history in two or more family members according to present evidence in the literature. It is also known that AIP mutation is usually associated with more aggressive clinical behavior due to unclarified reasons.

The prevalence of AIP mutation in Turkish population and types of mutations have not been defined previously. The primary aim of the present study is to define the AIP gene mutation prevalence and the relation with clinical and tumour behaviour in a subgroup of Turkish acromegalic patients. If AIP gene mutation is detected in some patients, it will be possible to screen the family of the patient for the presence of AIP mutation or at least for the presence of pituitary adenoma.

Acromegalic patients who are followed in Erciyes University Medical School Department of Endocrinology will be enrolled into the study. After DNA isolation, each exon of AIP gene including splicing points will be reproduced by polymerase chain reaction (PCR) and will be analyzed for the presence of mutation by sequence analysis. The cases will be analyzed further in means of clinical features according to presence of AIP gene mutation.

The prevalence of AIP gene mutation, clinical reflection of presence of AIP mutation will be determined and genetic consultation will be given to the carriers of AIP gene mutation at the end of the study.

Study Overview

Status

Unknown

Conditions

Acromegaly

Detailed Description

Screening for AIP gene mutation is recommended in patients with pituitary adenomas of childhood-onset, GH or PRL secreting tumors who are diagnosed before the age of 30 years and positive family history in two or more family members according to present evidence in the literature. It is also known that AIP mutation is usually associated with more aggressive clinical behavior due to unclarified reasons.

The prevalence of AIP mutation in Turkish population and types of mutations have not been defined previously. The primary aim of the present study is to define the AIP gene mutation prevalence and the relation with clinical and tumour behavior in a subgroup of Turkish acromegalic patients. If AIP gene mutation is detected in some patients, it will be possible to screen the family of the patient for the presence of AIP mutation or at least for the presence of pituitary adenoma.

Acromegalic patients who are followed in Erciyes University Medical School Department of Endocrinology will be enrolled into the study. The clinical and laboratory data will be recorded and the remission status of the patients will be determined. Each exon of AIP gene including splicing points will be reproduced by PCR and will be analyzed for the presence of mutation by sequence analysis. Genomic DNA will be isolated from peripheral blood samples of acromegalic patients by using the QIAamp DNA blood mini kit (QIA-GEN, Milano, Italy) according to the manufacturer's instruction. Fifty nanograms of genomic DNA will be ampliﬁed with primers as reported. The entire AIP gene will be examined acromegaly patients and healthy control group. Each AIP exon from each DNA sample will be ampliﬁed using PCR. Six AIP exons will be ampliﬁed using the Thermo Taq DNA polymerase and following conditions: an initial denaturation at 96°C for 5 min, followed by 34 cycles of 94°C for 45 s, 60°C for 45 s, 72°C for 1 min, then a ﬁnal extension step at 72°C for 7 min.PCR ampliﬁcations will be checked on a 2 % agarose gel. PCR products will be purified by PCR purification kit. Sequential alterations will be determined by bidirectional sequencing. Six AIP exons will be sequenced by using Beckman CEQ 8000.

The cases will be analyzed further in means of clinical features according to presence of AIP gene mutation.

Study Type

Observational

Enrollment (Anticipated)

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Turkey
- - Kayseri, Turkey, 38030
    - Recruiting
    - Erciyes University Medical School Department of Endocrinology
    - Contact:
      
      Fahrettin Kelestimur, Prof
      
      Phone Number: 00903524374922
      
      Email: fktimur@erciyes.edu.tr
    - Principal Investigator:
      
      Zuleyha Karaca, Assoc Prof
    - Principal Investigator:
      
      Serpil Taheri, Assis Prof
    - Sub-Investigator:
      
      Fatih Tanriverdi, Assoc Prof
    - Sub-Investigator:
      
      Kursad Unluhizarci, Prof
    - Principal Investigator:
      
      Fahrettin Kelestimur, Prof

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

acromegaly patients

Description

Inclusion Criteria:

* Patients with acromegaly

Exclusion Criteria:

* Patients with acromegaly due to ectopic GH or GHRH secreting tumors

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Observational Models: Cohort
Time Perspectives: Cross-Sectional

Number of groups / cohorts

Cohorts and Interventions

Group / Cohort
patients with acromegaly patients with acromegaly caused by a growth hormone secreting pituitary adenoma
healthy control healthy volunteers without a personal or family history of pituitary adenoma

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
number of acromegalic patients with AIP mutation Time Frame: up to 18 months	up to 18 months

Secondary Outcome Measures

Outcome Measure	Time Frame
number of acromegalic patients with aggressive tumor with AIP mutation Time Frame: up to 18 months	up to 18 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

TC Erciyes University

Investigators

Principal Investigator: Zuleyha Karaca, Erciyes University Medical School Department of Endocrinology Kayseri/Turkey
Principal Investigator: Serpil Taheri, Erciyes University Medical School Department of Medical Biology, Kayseri/Turkey
Study Director: Fahrettin Kelestimur, Erciyes University Medical School Department of Endocrinology Kayseri/Turkey
Study Chair: Fatih Tanriverdi, Erciyes University Medical School Department of Endocrinology Kayseri/Turkey
Study Chair: Kursad Unluhizarci, Erciyes University Medical School Department of Endocrinology Kayseri/Turkey

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2012

Primary Completion (Anticipated)

August 1, 2014

Study Completion (Anticipated)