AIP NM_003977.4:c.910C>T, Arg304Ter

The p.R304* pathogenic mutation (also known as c.910C>T), located in coding exon 6 of the AIP gene, results from a C to T substitution at nucleotide position 910. This changes the amino acid from an arginine to a stop codon within coding exon 6. This alteration has been well described in numerous individuals with personal and/or family history consistent with AIP-Related Familial Isolated Pituitary Adenomas (Vierimaa O et al. Science, 2006 May;312:1228-30; Georgitsi M et al. Proc. Natl. Acad. Sci. U.S.A., 2007 Mar;104:4101-5; Daly AF et al. J. Clin. Endocrinol. Metab., 2007 May;92:1891-6; Chahal HS et al. N. Engl. J. Med., 2011 Jan;364:43-50; Cuny T et al. Eur. J. Endocrinol., 2013 Apr;168:533-41; Niyazoglu M et al. Pituitary, 2014 Jun;17:220-6; Radian S et al. Hum. Mutat., 2017 01;38:78-85). Haplotype studies have concluded this alteration to be both an Italian and Irish founder mutation (Occhi G et al. J. Endocrinol. Invest., 2010 Dec;33:800-5; Chahal HS et al. N. Engl. J. Med., 2011 Jan;364:43-50); however, given the presence of this alteration in other populations, including Turkish and Mexican, who do not share a common haplotype, it has been suggested that this alteration may arise from independent, recurring mutational events (Ramírez-Rentería C et al. Endocrine, 2016 Aug;53:402-11). Functional analysis of the effect of this alteration on cell proliferation has shown reduced ability to block cell proliferation compared with wild-type AIP (Leontiou CA et al. J. Clin. Endocrinol. Metab., 2008 Jun;93:2390-401). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of AIP, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 27 amino acids of the protein. While the exact functional impact of these removed amino acids is unknown at this time, the final carboxy-terminal amino acids are presumed necessary for interactions of AIP with heat shock protein 90 (hsp90) and the aryl hydrocarbon receptor (AhR) (Petrulis JR et al. Chem. Biol. Interact., 2002 Sep;141:25-40; Daly AF et al. J. Clin. Endocrinol. Metab., 2007 May;92:1891-6). As such, this alteration is interpreted as a disease-causing mutation.

This sequence change creates a premature translational stop signal (p.Arg304*) in the AIP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the AIP protein. This variant is present in population databases (rs104894195, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with pituitary adenomas and pituitary adenomas and acromegaly (PMID: 16728643, 18381572, 20354355, 21208107, 23321498, 23743763, 27033541, 27650164). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4888). For these reasons, this variant has been classified as Pathogenic.