OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome
Authors: Lydie Burglen
Christel Thauvin-Robinet
Brunella Franco
Stéphane Audebert
Olivier Rosnet
Daniel Isnardon
Angélique Bole
Frédérique Lembo
Ange-Line Bruel
Véronique Chevrier
Jean-Baptiste Rivière
Teunis J P Van Dam
Paul Kuentz
Daniel Birnbaum
Emilie Baudelet
Jean-Paul Borg
Martijn A Huynen
Julien Thevenon
Melissa Lo Scalzo
Laurence Faivre
Journal: Human Molecular Genetics (2016)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Oral-facial-digital syndromes; OFD VI syndrome; KIAA0753/OFIP; centrioles; primary cilia
Affiliations: Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, Institut Paoli-Calmettes and CNRS U7258, F-13009 Marseille, France, Aix-Marseille Université, F-13007 Marseille, France., Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université Fédérale Bourgogne - Franche Comté, F-21079 Dijon, France, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD)., Centre for Molecular and Biomolecular Informatics, Radboud University Medical Centre, Nijmegen, The Netherlands., Telethon Institute of Genetics and Medicine, Naples, Italy, Medical Genetics, Department of Medical Translational Sciences, University of Napoli Federico II, Naples, Italy., All Children Hospital, Saint Petersburg, FL, USA., Aix-Marseille Université, F-13007 Marseille, France., Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université Fédérale Bourgogne - Franche Comté, F-21079 Dijon, France, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est., Centre de Référence des Malformations et Maladies Congénitales du Cervelet and Service de Génétique, Hôpital Armand Trousseau, AP-HP, Paris, France., Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université Fédérale Bourgogne - Franche Comté, F-21079 Dijon, France, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Laboratoire de Génétique Moléculaire, Plateau Technique de Biologie, Centre Hospitalier Universitaire Dijon, Dijon F-21079, France., Centre de Recherche en Cancérologie de Marseille, INSERM UMR1068, Institut Paoli-Calmettes and CNRS U7258, F-13009 Marseille, France, Aix-Marseille Université, F-13007 Marseille, France,  ., Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université Fédérale Bourgogne - Franche Comté, F-21079 Dijon, France, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est,  .

Abstract:  Oral-facial-digital (OFD) syndromes are rare heterogeneous disorders characterized by the association of abnormalities of the face, the oral cavity and the extremities, some due to mutations in proteins of the transition zone of the primary cilia or the closely associated distal end of centrioles. These two structures are essential for the formation of functional cilia, and for signaling events during development. We report here causal compound heterozygous mutations of KIAA0753/OFIP in a patient with an OFD VI syndrome. We show that the KIAA0753/OFIP protein, whose sequence is conserved in ciliated species, associates with centrosome/centriole and pericentriolar satellites in human cells and forms a complex with FOR20 and OFD1. The decreased expression of any component of this ternary complex in RPE1 cells causes a defective recruitment onto centrosomes and satellites. The OFD KIAA0753/OFIP mutant loses its capacity to interact with FOR20 and OFD1, which may be the molecular basis of the defect. We also show that KIAA0753/OFIP has microtubule-stabilizing activity. OFD1 and FOR20 are known to regulate the integrity of the centriole distal end, confirming that this structural element is a target of importance for pathogenic mutations in ciliopathies. 

Retracted: No

PubPeer comments:
 One case of OFD with mutation of *KIAA0753* ![file] The authors choose to illustrate molar tooth sign by using the same section (on T1 and T2). A sagittal section would be greatly appreciated to better see the vermis. Thank you for providing this section. ,