OR25-07 A Novel and Severe Multisystem Metabolic Disease due to Homozygous AIP Variants

Abstract

Abstract Disclosure: M. Korbonits: Novo Nordisk, Ipsen, Pfizer, Inc.. X. Wang: None. S. Barry: None. O. Suleyman: None. D. Stefano: None. N. Uddin: None. C.L. Hall: None. P. Laura: None. P. Chapple: None. H. Sian: None. V. Morales: None. K. Bianchi: None. M. Duchen: None. S. Patel: None. E. Aksoy: None. G. Czibik: None. A. Borovikov: None. H. Björnsson: None. H. Van Esch: None. S. Tooze: None. C. Brennan: None. O. Haworth: None. Background: The aryl hydrocarbon receptor interacting protein (AIP) is a highly conserved and ubiquitously expressed chaperone protein. For over a decade, heterozygous loss-of-function mutations in the AIP gene have been linked to childhood-onset pituitary adenomas. Our data here reveal that AIP is vital for metabolic processes, well beyond its role in the pituitary gland. Results - patients Biallelic loss of the Aip gene leads to embryonic (mouse) or larval (fruit file, C. elegans) lethality. Surprisingly, we identified children born with deleterious biallelic variants of AIP. These variants include three distinct homozygous mutations across four kindreds. Two of these variants are absent in the gnomAD variant database, while the third one has a minor allele frequency (MAF) of 0.000003097, identified only in heterozygote state. In the first family, consanguineous, two close relatives were affected. Two of the 4 kindreds (with the same variant) were from the same geographical area. The affected patients have a severe multisystem metabolic disorder characterized by failure to thrive following birth. Two children died before their first birthday ultimately of heart failure. The patients show non-infectious hyperthermia, hypercalcaemia, hypercalciuria with nephrocalcinosis, chronic diarrhoea, tachycardia, hypertension and delayed development. Results -experimental Using patient-derived dermal fibroblasts and Aip knockout mouse embryonic fibroblasts, we have discovered that AIP was required to support proteasome activity, induction of autophagy, lysosome function, maintaining metabolic homeostasis during periods of excessive metabolic demand. aip knockout zebrafish recapitulated the severe phenotype of the children, exhibiting cardiomegaly and death after yolk depletion when autophagy is required for cells to adapt to periods of starvation. Our results demonstrate that AIP plays a crucial role in initiating autophagy to maintain proteostasis in response to nutrient deprivation and during periods of high metabolic demand. In summary, we have identified a novel and complex paediatric disorder linked to biallelic AIP variants. Furthermore, we have in part uncovered the molecular mechanisms contributing to the severe phenotype, highlighting AIP’s critical role in autophagy and metabolic regulation. Presentation: Monday, July 14, 2025