WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells.
Mara Cavallin
(1, 2, 3)
,
Maria A Rujano
(1, 2)
,
Nathalie Bednarek
(4)
,
Daniel Medina-Cano
(2, 1)
,
Antoinette Bernabe Gelot
(5, 1)
,
Séverine Drunat
(1)
,
Camille Maillard
(1, 2)
,
Meriem Garfa-Traore
(1)
,
Christine Bole
(1)
,
Patrick Nitschke
(1)
,
Claire Beneteau
(6)
,
Thomas Besnard
(6)
,
Benjamin Cogné
(6)
,
Marion Eveillard
(6)
,
Alice Kuster
(7)
,
Karine Poirier
(1, 8)
,
Alain Verloes
(1, 9, 10)
,
Jelena Martinovic
(11)
,
Laurent Bidat
(12)
,
Marlène Rio
(3)
,
Stanislas Lyonnet
(1, 2)
,
M Louise Reilly
(2, 1, 10)
,
Nathalie Boddaert
(3, 1)
,
Melanie Jenneson-Liver
(4)
,
Jacques Motte
(4)
,
Martine Doco-Fenzy
(13)
,
Jamel Chelly
(14)
,
Tania Attie-Bitach
(1, 2, 3)
,
Matias Simons
(2, 1)
,
Vincent Cantagrel
(2, 1)
,
Sandrine Passemard
(1, 9, 10)
,
Alexandre Baffet
(15)
,
Sophie Thomas
(1, 2)
,
Nadia Bahi-Buisson
(1, 2, 3)
1
INSERM -
Institut National de la Santé et de la Recherche Médicale
2 UPD5 - Université Paris Descartes - Paris 5
3 Hôpital Necker - Enfants Malades [AP-HP]
4 CHU Reims - Hôpital universitaire Robert Debré [Reims]
5 CHU Trousseau [APHP]
6 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
7 PhAN - Physiopathologie des Adaptations Nutritionnelles
8 CNRS - Centre National de la Recherche Scientifique
9 Sorbonne Universités (COMUE)
10 UPD7 - Université Paris Diderot - Paris 7
11 AP-HP - Hôpital Antoine Béclère, Assistance Publique - Hôpitaux de Paris
12 Centre Hospitalier René Dubos [Pontoise]
13 Hôpital Maison Blanche
14 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
15 Institut Curie [Paris]
2 UPD5 - Université Paris Descartes - Paris 5
3 Hôpital Necker - Enfants Malades [AP-HP]
4 CHU Reims - Hôpital universitaire Robert Debré [Reims]
5 CHU Trousseau [APHP]
6 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
7 PhAN - Physiopathologie des Adaptations Nutritionnelles
8 CNRS - Centre National de la Recherche Scientifique
9 Sorbonne Universités (COMUE)
10 UPD7 - Université Paris Diderot - Paris 7
11 AP-HP - Hôpital Antoine Béclère, Assistance Publique - Hôpitaux de Paris
12 Centre Hospitalier René Dubos [Pontoise]
13 Hôpital Maison Blanche
14 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
15 Institut Curie [Paris]
Nathalie Bednarek
- Fonction : Auteur
- PersonId : 741616
- IdHAL : nathalie-bednarek-weirauch
- IdRef : 10370793X
Séverine Drunat
- Fonction : Auteur
- PersonId : 761936
- ORCID : 0000-0003-1744-3206
Thomas Besnard
- Fonction : Auteur
- PersonId : 171787
- IdHAL : tombesnard
- ORCID : 0000-0003-4804-5147
Benjamin Cogné
- Fonction : Auteur
- PersonId : 776524
- ORCID : 0000-0002-5503-6292
Marion Eveillard
- Fonction : Auteur
- PersonId : 781636
- ORCID : 0000-0001-7206-5135
Alain Verloes
- Fonction : Auteur
- PersonId : 757590
- ORCID : 0000-0003-4819-0264
Nathalie Boddaert
- Fonction : Auteur
- PersonId : 759620
- ORCID : 0000-0003-0991-7774
- IdRef : 089425561
Martine Doco-Fenzy
- Fonction : Auteur
- PersonId : 1115002
- ORCID : 0000-0001-7429-6201
- IdRef : 075681404
Vincent Cantagrel
- Fonction : Auteur
- PersonId : 772235
- ORCID : 0000-0002-5180-4848
- IdRef : 117651877
Sandrine Passemard
- Fonction : Auteur
- PersonId : 759229
- ORCID : 0000-0002-0242-4566
Résumé
Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.