Borealin/CDCA8 deficiency alters thyroid development and results in papillary tumor-like structures

Hortense Didier-Mathon; Athanasia Stoupa; Dulanjalee Kariyawasam; Sonny Yde; Beatrix Cochant-Priollet; Lionel Groussin; Frédéric Sébag; Nicolas Cagnard; Patrick Nitschke; Dominique Luton; Michel Polak; Aurore Carré

doi:10.3389/fendo.2023.1286747

Borealin/CDCA8 deficiency alters thyroid development and results in papillary tumor-like structures

Front Endocrinol (Lausanne). 2023 Oct 27:14:1286747. doi: 10.3389/fendo.2023.1286747. eCollection 2023.

Authors

Hortense Didier-Mathon¹, Athanasia Stoupa^{1

2

3}, Dulanjalee Kariyawasam^{1

2

3}, Sonny Yde¹, Beatrix Cochant-Priollet^{4

5}, Lionel Groussin⁶, Frédéric Sébag⁷, Nicolas Cagnard⁸, Patrick Nitschke⁸, Dominique Luton⁹, Michel Polak^{1

2

3

10

11}, Aurore Carré^{1

2}

Affiliations

¹ Université Paris Cité, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin, Paris, France.
² IMAGINE Institute Affiliate, Paris, France.
³ Pediatric Endocrinology, Gynecology and Diabetology Department, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique Hopitaux de Paris (AP-HP), Paris, France.
⁴ Université Paris Cité, Faculté de Médecine, Paris, France.
⁵ Department of Pathology, Cochin Hospital, Assistance Publique Hopitaux de Paris (AP-HP) Centre, Paris, France.
⁶ Department of Endocrinology, Université Paris Cité, Cochin Hospital, Assistance Publique Hopitaux de Paris (AP-HP) Centre, Paris, France.
⁷ Endocrine Surgery, Conception University Hospital, Aix-Marseille University, Marseille, France.
⁸ Bioinformatics Platform, Institut Imagine, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Paris, France.
⁹ Département de Gynécologie Obstétrique, Hôpital Bicêtre, Assistance Publique Hopitaux de Paris (AP-HP) Le Kremlin Bicêtre France, Université Paris Saclay, Le Kremlin Bicêtre, France.
¹⁰ Centre de référence des maladies endocriniennes rares de la croissance et du développement, Necker-Enfants Malades University Hospital, Paris, France.
¹¹ Centre régional de dépistage néonatal (CRDN) Ile de France, Paris, France.

Abstract

Background: BOREALIN/CDCA8 mutations are associated with congenital hypothyroidism and thyroid dysgenesis. Borealin is involved in mitosis as part of the Chromosomal Passenger Complex. Although BOREALIN mutations decrease thyrocyte adhesion and migration, little is known about the specific role of Borealin in the thyroid.

Methods: We characterized thyroid development and function in Borealin-deficient (Borealin ^+/-) mice using histology, transcriptomic analysis, and quantitative PCR.

Results: Thyroid development was impaired with a hyperplastic anlage on embryonic day E9.5 followed by thyroid hypoplasia from E11.5 onward. Adult Borealin ^+/- mice exhibited euthyroid goiter and defect in thyroid hormone synthesis. Borealin ^+/- aged mice had disorganized follicles and papillary-like structures in thyroids due to ERK pathway activation and a strong increase of Braf-like genes described by The Cancer Genome Atlas (TCGA) network of papillary thyroid carcinoma. Moreover, Borealin ^+/- thyroids exhibited structural and transcriptomic similarities with papillary thyroid carcinoma tissue from a human patient harboring a BOREALIN mutation, suggesting a role in thyroid tumor susceptibility.

Conclusion: These findings demonstrate Borealin involvement in critical steps of thyroid structural development and function throughout life. They support a role for Borealin in thyroid dysgenesis with congenital hypothyroidism. Close monitoring for thyroid cancer seems warranted in patients carrying BOREALIN mutations.

Keywords: Borealin; congenital hypothyroidism; thyroid cancer; thyroid dysgenesis; thyroid function.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Cycle Proteins / genetics
Congenital Hypothyroidism* / genetics
Mice
Thyroid Cancer, Papillary / genetics
Thyroid Dysgenesis* / genetics
Thyroid Neoplasms* / genetics

Substances

CDCA8 protein, human
Cell Cycle Proteins
CDCA8 protein, mouse

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. HD-M was supported by the non-profit Fonds d’Etudes et de Recherche du Corps Médical (FERCM) and Assistance Publique-Hôpitaux de Paris (AP-HP). AC and MP received financial support from three corporations (EDF, Sandoz SAS, and Merck Serono France). The funders were not involved in the study design, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. AS was supported by a European Society for Paediatric Endocrinology Research Fellowship Grant and by the Alexander S. Onassis Foundation.