OR2802 A Novel CABLES1 Missense Variant Associated With Cushing's Disease Disrupts Protein Structure And Stability

Abstract Disclosure: A.L. Franco-Álvarez: None. M. Torres Morán: None. R.G. Rebollar-Vega: None. N. Pankratz: None. J. Lane: None. F.R. Faucz: None. P. Chittiboina: None. D.M. Kay: None. J.L. Mills: None. C.A. Stratakis: None. L.C. Hernández-Ramírez: None. Introduction. The adrenal-pituitary feedbac...

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Published in:Journal of the Endocrine Society 2023-10, Vol.7 (Supplement_1)
Main Authors: Franco-Álvarez, Alexa L, Morán, Mariana Torres, Rebollar-Vega, Rosa G, Pankratz, Nathan, Lane, John, Faucz, Fabio R, Chittiboina, Prashant, Kay, Denise M, Mills, James L, Stratakis, Constantine A, Hernández-Ramírez, Laura C
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Language:English
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Neuroendocrinology & Pituitary
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Summary:Abstract Disclosure: A.L. Franco-Álvarez: None. M. Torres Morán: None. R.G. Rebollar-Vega: None. N. Pankratz: None. J. Lane: None. F.R. Faucz: None. P. Chittiboina: None. D.M. Kay: None. J.L. Mills: None. C.A. Stratakis: None. L.C. Hernández-Ramírez: None. Introduction. The adrenal-pituitary feedback loop is disrupted in Cushing's disease (CD). One of the glucocorticoid-responsive genes participating in this regulatory pathway is the negative cell cycle regulator CABLES1. We have previously reported five germline missense CABLES1 variants associated with CD and macroadenomas: two in young adults (p.E178K and p.L240F), two in children (p.G312D and p.D463G), and one in a middle-aged adult (p.P31L). The first four variants resulted in loss of the cell growth inhibition activity, but the fifth one has not been functionally validated. Aims. To report in detail a case of CD associated with the CABLES1 p.P31L variant and to characterize the molecular consequences of this variant using in silico and in vitro approaches. Methods. Variant detection was done via exome sequencing. Immunohistochemistry for CDKN1B and CABLES1 was performed on pituitary tumor slides. Loss of heterozygosity for CABLES1 p.P31L and common somatic variants were investigated in the tumor tissue. Protein stability studies were done for the CABLES1 variants p.P31L, p.L240F, p.G312D and p.D463G transiently expressed in HEK293 cells, using the cycloheximide chase method. The interaction of the CABLES1 variants with CDK2 was analyzed by transient expression in HEK293 cells and co-immunoprecipitation. Results. The p.P31L variant was found in a 53-year-old woman with CD. She achieved remission after resection of a macroadenoma (reported as a null-cell tumor). Recurrence one year later prompted a reintervention, and this a 60 mm Crooke cell adenoma was resected, again with postoperative remission. The p.P31L variant is of uncertain significance according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. The affected residue (P31) is part of a PPP motif that lies within a proline-rich region of CABLES1 (residues 30-52) within the N-terminal disorder, with unknown functional role. By immunohistochemistry, the corticotropinoma retained CABLES1 expression, but had lost 70% of CDKN1B expression. Loss of heterozgosity for CABLES1 p.P31L, as well as and hotspot BRAF, USP8, and USP48 were negative in the tumor. The p.P31L variant had an increased d
ISSN:2472-1972
2472-1972
DOI:10.1210/jendso/bvad114.1364