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Nat Genet. 2014 Aug;46(8):905-11. doi: 10.1038/ng.3031. Epub 2014 Jul 6.

The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation.

Author information

1
1] Equipe d'Accueil 4271 Génétique des Anomalies du Développement, Fédération Hospitalo-Universitaire, Université de Bourgogne, Dijon, France. [2] Centre de Référence Maladies Rares "Anomalies du Développement et Syndromes Malformatifs" de l'Est, Centre de Génétique et Pédiatrie 1, Hôpital d'Enfants, Centre Hospitalier Universitaire Dijon, Dijon, France. [3].
2
1] Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA. [2].
3
Equipe d'Accueil 4271 Génétique des Anomalies du Développement, Fédération Hospitalo-Universitaire, Université de Bourgogne, Dijon, France.
4
1] Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universitat de València, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas, Valencia, Spain. [2] Unidad Mixta de Esclerosis Múltiple y Neurorregeneración, Instituto de Investigación Sanitaria Hospital La Fe, Universitat de València, Valencia, Spain.
5
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA.
6
1] Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy. [2] Department of Medical Translational Sciences, Division of Pediatrics, Federico II University of Naples, Naples, Italy.
7
Centre de Référence Maladies Rares "Anomalies du Développement et Syndromes Malformatifs" de l'Ouest, Unité Fonctionnelle de Génétique Médicale, Centre Hospitalier Universitaire Rennes, Rennes, France.
8
Laboratoire d'Anatomie-Pathologie, Centre Hospitalier Universitaire Rennes, Rennes, France.
9
1] Equipe d'Accueil 4271 Génétique des Anomalies du Développement, Fédération Hospitalo-Universitaire, Université de Bourgogne, Dijon, France. [2] Laboratoire de Génétique Moléculaire, Plateau Technique de Biologie, Centre Hospitalier Universitaire Dijon, Dijon, France.
10
Department of Biochemistry, University of Leicester, Leicester, UK.
11
1] Equipe d'Accueil 4271 Génétique des Anomalies du Développement, Fédération Hospitalo-Universitaire, Université de Bourgogne, Dijon, France. [2] Centre de Référence Maladies Rares "Anomalies du Développement et Syndromes Malformatifs" de l'Est, Centre de Génétique et Pédiatrie 1, Hôpital d'Enfants, Centre Hospitalier Universitaire Dijon, Dijon, France.
12
1] INSERM U781, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France. [2] Paris Descartes-Sorbonne Paris Cité University, Institut IMAGINE, Paris, France.
13
1] INSERM U781, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France. [2] Paris Descartes-Sorbonne Paris Cité University, Institut IMAGINE, Paris, France. [3] Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France.
14
1] Paris Descartes-Sorbonne Paris Cité University, Institut IMAGINE, Paris, France. [2] INSERM, UMRS 1163, Laboratory of Inherited Kidney Diseases, Paris, France.
15
Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon.

Abstract

Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia. How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth, whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation. Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.

PMID:
24997988
PMCID:
PMC4120243
DOI:
10.1038/ng.3031
[Indexed for MEDLINE]
Free PMC Article
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