New Research Highlights Possible Genetic Cause of Cushing's Disease

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Both pediatric and adult patients with Cushing’s disease were included in the study.
Both pediatric and adult patients with Cushing’s disease were included in the study.

New findings published in the journal Endocrine-Related Cancer provide evidence of loss-of-function mutations in the CABLES1 gene causing Cushing's disease, suggesting to researchers that CABLES1 may represent a novel pituitary tumor-predisposing gene.

The study included samples of 146 pediatric (118 germline DNA only; 28 germline and tumor DNA) and 35 adult (tumor DNA) patients with Cushing's disease. In the pediatric population, 50.7% were female and the mean age at diagnosis was 12.5 years; in the adult cohort, 71.4% were female and the mean age at diagnosis was 44 years.

 

The researchers screened patients for CABLES1 mutations and evaluated copy number variations in 145 pediatric patients (87 germline DNA only; 29 germline and tumor DNA).

According to the results, the analysis led to the identification of 4 potentially pathogenic missense variants in CABLES1, 2 of which were found in children with Cushing's disease and 2 in young adults with Cushing's disease. No copy number variations were reported.

Furthermore, researchers observed that the 4 missense variants had an impact on residues within or near the predicted cyclin-dependent kinase-3-binding region of the CABLES1 protein, and compromised its ability to block cell growth in a mouse corticotropinoma cell line. They also noted that the 4 patients had macroadenomas.

In addition to providing evidence of the role of CABLE1 as a novel pituitary tumor-predisposing gene, the researchers wrote that the findings demonstrate that the gene's function “might link 2 of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway."

“Further studies are needed,” they added, “to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas, and to elucidate the pituitary-specific functions of this gene.”

Reference

Hernández-Ramírez LC, Gam R, Valdés N, et al. Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease [published online May 22, 2017]. Endocr Relat Cancer. doi:10.1530/erc-17-0131

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