A potential contributory role for ciliary dysfunction in the 16p11.2 600 kb BP4-BP5 pathology

Eugenia Migliavacca, Christelle Golzio, Katrin Männik, Ian Blumenthal, Edwin C. Oh, Louise Harewood, Jack A. Kosmicki, Maria Nicla Loviglio, Giuliana Giannuzzi, Loyse Hippolyte, Anne M. Maillard, Ali Abdullah Alfaiz, Robert Witwicki, Gérard Didelot, Ilse Van Der Werf, Ali A. Alfaiz, Marianna Zazhytska, Jacqueline Chrast, Aurélien Macé, Sven BergmannZoltan Kutalik, Vanessa Siffredi, Flore Zufferey, Danielle Martinet, Frédérique Bena, Anita Rauch, Sonia Bouquillon, Bruno Delobel, Odile Boute, Bénédicte Duban-Bedu, Cédric Le Caignec, Bertrand Isidor, Jean Chiesa, Boris Keren, Brigitte Gilbert-Dussardier, Renaud Touraine, Dominique Campion, Caroline Rooryck Thambo, Michèle Mathieu-Dramard, Ghislaine Plessis, Frank Kooy, Hilde Peeters, Katrin Ounap, Anneke T. Vulto-Van Silfhout, Bert B. De Vries, Ellen Van Binsbergen, Ann Nordgren, Mafalda Mucciolo, Alessandra Renieri, Evica Rajcan-Separovic, John A. Philipps, Richard J. Ellis, Mieke M. Van Haelst, Joris Andrieux, James F. Gusella, Mark J. Daly, Jacques S. Beckmann, Sébastien Jacquemont, Michael E. Talkowski, Elias Nicholas Katsanis*, Alexandre Reymond

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs.

Original languageEnglish (US)
Pages (from-to)784-796
Number of pages13
JournalAmerican journal of human genetics
Volume96
Issue number5
DOIs
StatePublished - May 7 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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