TY - JOUR
T1 - Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease
AU - Hernández-Ramírez, Laura C.
AU - Gam, Ryhem
AU - Valdés, Nuria
AU - Lodish, Maya B.
AU - Pankratz, Nathan
AU - Balsalobre, Aurelio
AU - Gauthier, Yves
AU - Faucz, Fabio R.
AU - Trivellin, Giampaolo
AU - Chittiboina, Prashant
AU - Lane, John
AU - Kay, Denise M.
AU - Dimopoulos, Aggeliki
AU - Gaillard, Stephan
AU - Neou, Mario
AU - Bertherat, Jérôme
AU - Assié, Guillaume
AU - Villa, Chiara
AU - Mills, James L.
AU - Drouin, Jacques
AU - Stratakis, Constantine A.
N1 - Publisher Copyright:
© 2017 The authors Printed in Great Britain.
PY - 2017/8
Y1 - 2017/8
N2 - The CABLES1 cell cycle regulator participates in the adrenal-pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing's disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cellline (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two 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 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.
AB - The CABLES1 cell cycle regulator participates in the adrenal-pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing's disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cellline (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two 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 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.
KW - Corticotropinoma
KW - Cushing's disease
KW - Germline mutation
KW - Whole-exome sequencing
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U2 - 10.1530/ERC-17-0131
DO - 10.1530/ERC-17-0131
M3 - Article
C2 - 28533356
AN - SCOPUS:85038431992
SN - 1351-0088
VL - 24
SP - 379
EP - 392
JO - Endocrine-related cancer
JF - Endocrine-related cancer
IS - 8
ER -