AIP Gene Mutations

AIP (Aryl Hydrocarbon Receptor Interacting Protein) is the name of the gene which causes pituitary adenomas in some families with acromegaly and occasionally prolactinomas, and very rarely with other types of pituitary adenomas. Childhood or young adult onset patients usually with acromegaly can also have mutations in the AIP gene without a known family history of pituitary adenoma.

DNA (Deoxyribose Nucleic Acid) is the coding molecule that allows human cells to replicate and function. Human DNA is organised into compact structures called chromosomes of which humans have 23 pairs. In each pair, one chromosome comes from the mother, and one from the father. Twenty-two pair of chromosomes are the autosomes and the 23rd pair that determines your gender (XY-male and XX-female). The AIP gene is located on the 11th chromosome (Figure 1). Patients with an AIP mutation have one normal copy of the gene and one abnormal copy. This is called a heterozygote state.

Figure 1. The AIP gene is located on Chromosome 11 (Chr 11)

Within your DNA there are streches of DNA called genes, which are sequences that code for specific proteins. The AIP gene codes for the AIP protein and it is synthetised in several types of cells including the cells of the pituitary gland.

AIP is thought to be a tumour suppressor gene. Its function is to keep the replication of the cell in order, preventing the development of tumours. In individuals with an AIP gene mutation, the function of the AIP gene is damaged and the mutation leads to have an increased chance to develop abnormally replicating cells, specially growth hromone and prolactin-secreting cells, and to develop an adenoma.

To date, around 50 different type of mutations (changes) have been identified throughout the AIP gene, causing the development of a pituitary adenoma. The majority of the mutations change the structure of the latter part of the AIP protein (marked with purple, blue, pink and red on Figure 2).

Figure 2. Human AIP showing the areas of the protein most often affected by mutations: the purple, blue, pink and red helicis.

The DNA consists of individual building blocks called bases, and a gene is formed by a particular sequence of these bases (Figure 3). At the beginning of the gene is a region called the promoter, which regulates how the gene is functioning. Following this is the protein coding gene sequence, which in AIP is approximately 1000 bases long, coding for a 330 amino acid long peptide. When a mutation occurs the sequence of the bases changes and this will result in a change of the protein coded by the gene.

Figure 3. The structure of DNA

There are different types of mutations in the AIP gene:

• Missense Mutations: These mutations cause a change in a basepair resulting in a change of an amino acid and therefore a difference in the protein sequence of the AIP protein.
• Nonsense Mutations: This is when the mutation causes insertion of a stop codon, causing the AIP protein to be much shorter than it should be. This has a major effect on the AIP protein function.
• In-Frame Deletions/Insertions: This is when one, or more whole codons are deleted/inserted, resulting in a decrease/increase in the length of the AIP protein.
• Frameshift Mutations: This is when one, or two bases are deleted/inserted, causing the whole codon reading frame to shift, changing the every codon and therefore every amino acid following the mutation.
• Promoter Mutations: This is a mutation in the promoter region that affects the regulation of the gene.
• Large Deletions: This is when a large segment of the gene is deleted, resulting in the AIP protein being severely altered.
• Splice Site Mutations: These mutations affect the assembly of the gene and abnormalities caused by splice site mutations usually severely disrupt the structure of the protein.

The location and type of AIP variants described can be seen on the next figure (Figure 4).

Figure 4. The location and type of AIP variants identified in patients with AIP changes. In the middle the thick black line and the black and white boxes (Exon 1-6) represent the AIP gene on Chromosome 11 (Chr 11). The blue thin arrows show the location of the AIP mutations and their 'name' (identification code) in colourful boxes representing the different types of mutations