Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease

Laura C. Hernández-Ramírez; Ryhem Gam; Nuria Valdés; Maya B. Lodish; Nathan Pankratz; Aurelio Balsalobre; Yves Gauthier; Fabio R. Faucz; Giampaolo Trivellin; Prashant Chittiboina; John Lane; Denise M. Kay; Aggeliki Dimopoulos; Stephan Gaillard; Mario Neou; Jérôme Bertherat; Guillaume Assié; Chiara Villa; James L. Mills; Jacques Drouin; Constantine A. Stratakis

doi:10.1530/ERC-17-0131

Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease

Laura C. Hernández-Ramírez, Ryhem Gam, Nuria Valdés, Maya B. Lodish, Nathan Pankratz, Aurelio Balsalobre, Yves Gauthier, Fabio R. Faucz, Giampaolo Trivellin, Prashant Chittiboina, John Lane, Denise M. Kay, Aggeliki Dimopoulos, Stephan Gaillard, Mario Neou, Jérôme Bertherat, Guillaume Assié, Chiara Villa, James L. Mills, Jacques DrouinConstantine A. Stratakis

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

63 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	379-392
Number of pages	14
Journal	Endocrine-related cancer
Volume	24
Issue number	8
DOIs	https://doi.org/10.1530/ERC-17-0131
State	Published - Aug 2017

Bibliographical note

Funding Information:
This work was supported by the Intramural Research Program, NICHD, NIH (DIR and DIPHR, NICHD and contract HHSN275201300023I), grants from the Canadian Institutes of Health Research (R G, A N, Y G and J D) and by the Fondation Foch (Foch Hospital, Suresnes, France) (C V).

Funding Information:
We studied 146 pediatric (<18 years at diagnosis) patients with CD who are part of a large cohort evaluated at the outpatient clinic and/or admitted for clinical work-up and treatment at the National Institutes of Health (NIH) Clinical Center between 1997 and 2017 and recruited under the research protocol 97-CH-0076 (ClinicalTrials. gov: NCT00001595). The Eunice Kennedy Shriver National Institute of Child Health and Human Development Institutional Review Board approved this study, and informed assent/consent was obtained from all the patients and their parents/guardians. Clinical data were obtained directly from the patients and/or from the Clinical Research Information System. Parents and siblings of the patients were also recruited, when available.

Funding Information:
1Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA 2Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada 3Service of Endocrinology and Nutrition, Hospital Universitario Central de Asturias, Instituto Universita-rio de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain 4Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA 5Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, USA 6Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, New York, USA 7Division of Intramural Population Health Research, Epidemiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA 8Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France 9Department of Neurosurgery, Hôpital Foch, Suresnes, France 10Service d’Endocrinologie, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France 11Department of Pathological Cytology and Anatomy, Hôpital Foch, Suresnes, France 12Department of Endocrinology, CHU de Liège, University of Liège, Liège, Belgium *(J L Mills, J Drouin and C A Stratakis contributed equally to this work)

Publisher Copyright:
© 2017 The authors Printed in Great Britain.

Keywords

Corticotropinoma
Cushing's disease
Germline mutation
Whole-exome sequencing

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1530/ERC-17-0131

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510591

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Hernández-Ramírez, L. C., Gam, R., Valdés, N., Lodish, M. B., Pankratz, N., Balsalobre, A., Gauthier, Y., Faucz, F. R., Trivellin, G., Chittiboina, P., Lane, J., Kay, D. M., Dimopoulos, A., Gaillard, S., Neou, M., Bertherat, J., Assié, G., Villa, C., Mills, J. L., ... Stratakis, C. A. (2017). Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease. Endocrine-related cancer, 24(8), 379-392. https://doi.org/10.1530/ERC-17-0131

Hernández-Ramírez, LC, Gam, R, Valdés, N, Lodish, MB, Pankratz, N, Balsalobre, A, Gauthier, Y, Faucz, FR, Trivellin, G, Chittiboina, P, Lane, J, Kay, DM, Dimopoulos, A, Gaillard, S, Neou, M, Bertherat, J, Assié, G, Villa, C, Mills, JL, Drouin, J & Stratakis, CA 2017, 'Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease', Endocrine-related cancer, vol. 24, no. 8, pp. 379-392. https://doi.org/10.1530/ERC-17-0131

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title = "Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease",

abstract = "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.",

keywords = "Corticotropinoma, Cushing's disease, Germline mutation, Whole-exome sequencing",

author = "Hern{\'a}ndez-Ram{\'i}rez, {Laura C.} and Ryhem Gam and Nuria Vald{\'e}s and Lodish, {Maya B.} and Nathan Pankratz and Aurelio Balsalobre and Yves Gauthier and Faucz, {Fabio R.} and Giampaolo Trivellin and Prashant Chittiboina and John Lane and Kay, {Denise M.} and Aggeliki Dimopoulos and Stephan Gaillard and Mario Neou and J{\'e}r{\^o}me Bertherat and Guillaume Assi{\'e} and Chiara Villa and Mills, {James L.} and Jacques Drouin and Stratakis, {Constantine A.}",

note = "Funding Information: This work was supported by the Intramural Research Program, NICHD, NIH (DIR and DIPHR, NICHD and contract HHSN275201300023I), grants from the Canadian Institutes of Health Research (R G, A N, Y G and J D) and by the Fondation Foch (Foch Hospital, Suresnes, France) (C V). Funding Information: We studied 146 pediatric (<18 years at diagnosis) patients with CD who are part of a large cohort evaluated at the outpatient clinic and/or admitted for clinical work-up and treatment at the National Institutes of Health (NIH) Clinical Center between 1997 and 2017 and recruited under the research protocol 97-CH-0076 (ClinicalTrials. gov: NCT00001595). The Eunice Kennedy Shriver National Institute of Child Health and Human Development Institutional Review Board approved this study, and informed assent/consent was obtained from all the patients and their parents/guardians. Clinical data were obtained directly from the patients and/or from the Clinical Research Information System. Parents and siblings of the patients were also recruited, when available. Funding Information: 1Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA 2Laboratoire de G{\'e}n{\'e}tique Mol{\'e}culaire, Institut de Recherches Cliniques de Montr{\'e}al (IRCM), Montr{\'e}al, Qu{\'e}bec, Canada 3Service of Endocrinology and Nutrition, Hospital Universitario Central de Asturias, Instituto Universita-rio de Oncolog{\'i}a del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain 4Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA 5Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, USA 6Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, New York, USA 7Division of Intramural Population Health Research, Epidemiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA 8Institut Cochin, INSERM U1016, CNRS UMR8104, Universit{\'e} Paris Descartes, Paris, France 9Department of Neurosurgery, H{\^o}pital Foch, Suresnes, France 10Service d{\textquoteright}Endocrinologie, Cochin Hospital, Assistance Publique H{\^o}pitaux de Paris, Paris, France 11Department of Pathological Cytology and Anatomy, H{\^o}pital Foch, Suresnes, France 12Department of Endocrinology, CHU de Li{\`e}ge, University of Li{\`e}ge, Li{\`e}ge, Belgium *(J L Mills, J Drouin and C A Stratakis contributed equally to this work) Publisher Copyright: {\textcopyright} 2017 The authors Printed in Great Britain.",

year = "2017",

month = aug,

doi = "10.1530/ERC-17-0131",

language = "English (US)",

volume = "24",

pages = "379--392",

journal = "Endocrine-related cancer",

issn = "1351-0088",

publisher = "Society for Endocrinology",

number = "8",

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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 - Funding Information: This work was supported by the Intramural Research Program, NICHD, NIH (DIR and DIPHR, NICHD and contract HHSN275201300023I), grants from the Canadian Institutes of Health Research (R G, A N, Y G and J D) and by the Fondation Foch (Foch Hospital, Suresnes, France) (C V). Funding Information: We studied 146 pediatric (<18 years at diagnosis) patients with CD who are part of a large cohort evaluated at the outpatient clinic and/or admitted for clinical work-up and treatment at the National Institutes of Health (NIH) Clinical Center between 1997 and 2017 and recruited under the research protocol 97-CH-0076 (ClinicalTrials. gov: NCT00001595). The Eunice Kennedy Shriver National Institute of Child Health and Human Development Institutional Review Board approved this study, and informed assent/consent was obtained from all the patients and their parents/guardians. Clinical data were obtained directly from the patients and/or from the Clinical Research Information System. Parents and siblings of the patients were also recruited, when available. Funding Information: 1Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA 2Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada 3Service of Endocrinology and Nutrition, Hospital Universitario Central de Asturias, Instituto Universita-rio de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain 4Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA 5Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, USA 6Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, New York, USA 7Division of Intramural Population Health Research, Epidemiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA 8Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Paris, France 9Department of Neurosurgery, Hôpital Foch, Suresnes, France 10Service d’Endocrinologie, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France 11Department of Pathological Cytology and Anatomy, Hôpital Foch, Suresnes, France 12Department of Endocrinology, CHU de Liège, University of Liège, Liège, Belgium *(J L Mills, J Drouin and C A Stratakis contributed equally to this work) 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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UR - http://www.scopus.com/inward/citedby.url?scp=85038431992&partnerID=8YFLogxK

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 -

Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease

Abstract

Bibliographical note

Keywords

UN SDGs

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