title: Mutations in BOREALIN cause thyroid dysgenesis.
abstract: Congenital hypothyroidism is the most common neonatal endocrine disorder and is primarily caused by developmental abnormalities otherwise known as thyroid dysgenesis (TD). We performed whole exome sequencing (WES) in a consanguineous family with TD and subsequently sequenced a cohort of 134 probands with TD to identify genetic factors predisposing to the disease. We identified the novel missense mutations p.S148F, p.R114Q and p.L177W in the BOREALIN gene in TD-affected families. Borealin is a major component of the Chromosomal Passenger Complex (CPC) with well-known functions in mitosis. Further analysis of the missense mutations showed no apparent effects on mitosis. In contrast, expression of the mutants in human thyrocytes resulted in defects in adhesion and migration with corresponding changes in gene expression suggesting others functions for this mitotic protein. These results were well correlated with the same gene expression pattern analysed in the thyroid tissue of the patient with BOREALIN-p.R114W. These studies open new avenues in the genetics of TD in humans.
authors.affiliation: INSERM U1016, Cochin Institute, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|IMAGINE Institute affiliate, Paris, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Carré
authors.affiliation: IMAGINE Institute affiliate, Paris, France.|Pediatric Endocrinology, Gynecology and Diabetology Unit, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Athanasia
authors.initials: A
authors.lastname: Stoupa
authors.affiliation: INSERM U1016, Cochin Institute, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Pediatric Endocrinology, Gynecology and Diabetology Unit, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Dulanjalee
authors.initials: D
authors.lastname: Kariyawasam
authors.affiliation: IMAGINE Institute affiliate, Paris, France.
authors.forename: Manelle
authors.initials: M
authors.lastname: Gueriouz
authors.affiliation: INSERM U1016, Cochin Institute, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Ramond
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Monus
authors.affiliation: Pediatric Endocrinology Unit, Hôpital Universitaire Robert Debré, AP-HP, Paris, France.|RARE Disorder Center: Centre des Maladies Endocriniennes Rares de la Croissance.
authors.forename: Juliane
authors.initials: J
authors.lastname: Léger
authors.affiliation: Department of Digestive and Endocrine Surgery, Cochin Hospital, AP-HP, Université Paris Descartes, Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gaujoux
authors.affiliation: Department of General, Endocrine and Metabolic Surgery, Hopital de la Conception, Marseille, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Sebag
authors.affiliation: INSERM U1016, Cochin Institute, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Glaser
authors.affiliation: Pediatric Endocrinology Unit, Hôpital Universitaire Robert Debré, AP-HP, Paris, France.|RARE Disorder Center: Centre des Maladies Endocriniennes Rares de la Croissance.
authors.forename: Delphine
authors.initials: D
authors.lastname: Zenaty
authors.affiliation: Bioinformatics Platform, Paris Descartes University, IMAGINE Institute, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.affiliation: Genomic Platform, INSERM UMR 1163, Paris Descartes Sorbonne Paris Cite University, Imagine Institute, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: INSERM U1163, IMAGINE Institute, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Hubert
authors.affiliation: INSERM U1163, IMAGINE Institute, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Department of Genetics, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.affiliation: INSERM U1016, Cochin Institute, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Scharfmann
authors.affiliation: INSERM U1163, IMAGINE Institute, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Department of Genetics, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: INSERM U1163, IMAGINE Institute, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Besmond
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA.
authors.forename: William
authors.initials: W
authors.lastname: Taylor
authors.affiliation: INSERM U1016, Cochin Institute, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|IMAGINE Institute affiliate, Paris, France.|Pediatric Endocrinology, Gynecology and Diabetology Unit, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France.|RARE Disorder Center: Centre des Maladies Endocriniennes Rares de la Croissance.
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
mesh_terms: D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008938:Mitosis / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D050033:Thyroid Dysgenesis / Q000235:genetics* / Q000473:pathology
chemical_list: C490157:CDCA8 protein, human; D018797:Cell Cycle Proteins