The Oral-facial-digital Syndrome Gene C2CD3 Encodes a Positive Regulator of Centriole Elongation

Overview

Journal Nat Genet

Specialty Genetics

Date 2014 Jul 7

PMID 24997988

Citations 74

Authors

Christel Thauvin-Robinet

Jaclyn S Lee

Estelle Lopez

Vicente Herranz-Perez

Toshinobu Shida

Brunella Franco

Laurence Jego

Fan Ye

Laurent Pasquier

Philippe Loget

Nadege Gigot

Bernard Aral

Carla A M Lopes

Judith St-Onge

Ange-Line Bruel

Julien Thevenon

Susana Gonzalez-Granero

Caroline Alby

Arnold Munnich

Michel Vekemans

Frederic Huet

Andrew M Fry

Sophie Saunier

Jean-Baptiste Riviere

Tania Attie-Bitach

Jose Manuel Garcia-Verdugo

Laurence Faivre

Andre Megarbane

Maxence V Nachury

Affiliations

Soon will be listed here.

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.

Citing Articles

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