ANKRD11 associé à la déficience intellectuelle et à l'autisme régule la différenciation des dendrites via la voie de signalisation BDNF / TrkB

Aperçu: G.M.

L'haplo-insuffisance  de ANKRD11 en raison de mutations de suppression ou de troncature provoque le syndrome de KBG, un désordre génétique rare caractérisé par une déficience intellectuelle, un "trouble du spectre de l'autisme", et des anomalies craniofacial. Cependant, on sait peu de choses sur le rôle neurobiologique de ANKRD11 pendant le développement du cerveau.  

Ici, l'équipe montre que ANKRD11 régule la migration des neurones pyramidaux et la différenciation dendritique dans le cortex cérébral en développement. En utilisant une approche de manipulation in utero, nous avons trouvé que le knockdown de Ankrd11 retardait la migration radiale des neurones corticaux. Les neurones déficients en ANKRD11 présentaient une croissance et une ramification des dendrites nettement réduites ainsi qu'une morphologie anormale de la colonne dendritique. Ankrd11 knockdown a supprimé l'acétylation de molécules épigénétiques telles que p53 et Histone H3. De plus, les niveaux d'ARNm des gènes liés à la croissance de Trkb, Bdnf et neurites ont été régulés à la baisse dans les neurones corticaux déficients en ANKRD11. La région du promoteur Trkb était largement dépourvue d'Histone H3 et de p53 acétylées, et était plutôt occupée par MeCP2 et DNMT1. La surexpression de TrkB a sauvé la croissance anormale des dendrites dans ces cellules. 

Ces résultats démontrent un nouveau rôle pour ANKRD11 dans la différenciation des neurones au cours du développement du cerveau et suggèrent une modification épigénétique comme une caractéristique moléculaire clé sous-jacente au syndrome KBG.

Neurobiol Dis. 2017 Dec 21. pii: S0969-9961(17)30293-0. doi: 10.1016/j.nbd.2017.12.008.

ANKRD11 associated with intellectual disability and autism regulates dendrite differentiation via the BDNF/TrkB signaling pathway

Ka M¹, Kim WY².

Author information

1

Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198, United States.

2

Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198, United States. Electronic address: wooyang.kim@unmc.edu.

Abstract

Haploinsufficiency of ANKRD11 due to deletion or truncation mutations causes KBG syndrome, a rare genetic disorder characterized by intellectual disability, autism spectrum disorder, and craniofacial abnormalities. However, little is known about the neurobiological role of ANKRD11 during brain development. Here we show that ANKRD11 regulates pyramidal neuron migration and dendritic differentiation in the developing moue cerebral cortex. Using an in utero manipulation approach, we found that Ankrd11 knockdown delayed radial migration of cortical neurons. ANKRD11-deficient neurons displayed markedly reduced dendrite growth and branching as well as abnormal dendritic spine morphology. Ankrd11 knockdown suppressed acetylation of epigenetic molecules such as p53 and Histone H3. Furthermore, the mRNA levels of Trkb, Bdnf, and neurite growth-related genes were downregulated in ANKRD11-deficient cortical neurons. The Trkb promoter region was largely devoid of acetylated Histone H3 and p53, and was instead occupied with MeCP2 and DNMT1. Overexpression of TrkB rescued abnormal dendrite growth in these cells. Our findings demonstrate a novel role for ANKRD11 in neuron differentiation during brain development and suggest an epigenetic modification as a potential key molecular feature underlying KBG syndrome.

KEYWORDS:

ANKRD11; Arborization; Autism; BDNF; Dendrite; Dendritic spine; Histone acetylation; Intellectual disability; TrkB

PMID:29274743

DOI:10.1016/j.nbd.2017.12.008

L'haploinsuffisence pour les gènes ANKRD11 fait la différence entre les syndromes de microdélétion de KBG et 16q24.3: 12 nouveaux cas

Aperçu: G.M.

La suppression 16q24 impliquant le gène ANKRD11, allant de 137 kb à 2 Mb, a été associée à un syndrome de microdélétion caractérisé par une déficience cognitive variable, un trouble du spectre de l'autisme, des dysmorphies faciales avec des anomalies dentaires, des anomalies cérébrales affectant essentiellement le corps calleux et une faible taille.

 

Eur J Hum Genet. 2017 Apr 19. doi: 10.1038/ejhg.2017.49.

Haploinsufficiency for ANKRD11-flanking genes makes the difference between KBG and 16q24.3 microdeletion syndromes: 12 new cases

Novara F¹, Rinaldi B¹, Sisodiya SM^2,3, Coppola A⁴, Giglio S^5,6, Stanzial F⁷, Benedicenti F⁷, Donaldson A⁸, Andrieux J⁹, Stapleton R¹⁰, Weber A¹¹, Reho P¹, van Ravenswaaij-Arts C¹², Kerstjens-Frederikse WS¹², Vermeesch JR¹³, Devriendt K¹³, Bacino CA^14,15, Delahaye A^16,17,18, Maas SM^19,20, Iolascon A^21,22, Zuffardi O¹.

Author information

1

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

2

Department of Clinical and Experimental Epilepsy, NIHR University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, London, UK.

3

The Epilepsy Society, Chalfont-St-Peter, Bucks, UK.

4

Epilepsy Centre, Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy.

5

Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy.

6

Department of Biomedical Experimental and Clinical Sciences 'Mario Serio', Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.

7

Servizio di Consulenza Genetica, Centro Provinciale di Coordinamento della Rete delle Malattie Rare, Azienda Sanitaria dell'Alto-Adige, Bolzano, Italy.

8

Department of Clinical Genetics, St Michael's Hospital, Bristol, UK.

9

Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, France.

10

Genetic Health Service NZ-Northern Hub, Building 30 Auckland City Hospital, Auckland, New Zealand.

11

Merseyside and Cheshire Clinical Genetics Service, Liverpool Women's (NHS) Foundation Hospital Trust, Liverpool, UK.

12

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

13

Laboratory of Cytogenetics and Genome Research, Center of Human Genetics, KU Leuven, Leuven, Belgium.

14

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

15

Texas Children's Hospital, Houston, TX, USA.

16

INSERM, UMR 1141, Robert Debré University Hospital, Paris, France.

17

Cytogenetics Unit, AP-HP, Jean Verdier Hospital, Bondy, France.

18

Paris 13 University, Sorbonne Paris Cité, UFR SMBH, Bobigny, France.

19

Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.

20

Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

21

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.

22

CEINGE Biotecnologie Avanzate Scarl, Naples, Italy.

Abstract

16q24 deletion involving the ANKRD11 gene, ranging from 137 kb to 2 Mb, have been associated with a microdeletion syndrome characterized by variable cognitive impairment, autism spectrum disorder, facial dysmorphisms with dental anomalies, brain abnormalities essentially affecting the corpus callosum and short stature. On the other hand, patients carrying either deletions encompassing solely ANKRD11 or its loss-of-function variants were reported in association with the KBG syndrome, characterized by a very similar phenotype, including mild-to-moderate intellectual disability, short stature and macrodontia of upper incisors, with inter and intrafamilial variability. To assess whether the haploinsufficiency of ANKRD11-flanking genes, such as ZFPM1, CDH15 and ZNF778, contributed to either the severity of the neurological impairment or was associated with other clinical features, we collected 12 new cases with a 16q24.2q24.3 deletion (de novo in 11 cases), ranging from 343 kb to 2.3 Mb. In 11 of them, the deletion involved the ANKRD11 gene, whereas in 1 case only flanking genes upstream to it were deleted. By comparing the clinical and genetic features of our patients with those previously reported, we show that the severity of the neurological phenotype and the frequency of congenital heart defects characterize the deletions that, besides ANKRD11, contain ZFPM1, CDH15 and ZNF778 as well. Moreover, the presence of thrombocytopenia and astigmatism should be taken into account to distinguish between 16q24 microdeletion syndrome and KBG syndrome. The single patient not deleted for ANKRD11, whose phenotype is characterized by milder psychomotor delay, cardiac congenital malformation, thrombocytopenia and astigmatism, confirms all this data.European Journal of Human Genetics advance online publication, 19 April 2017; doi:10.1038/ejhg.2017.49.

PMID: 28422132

DOI: 10.1038/ejhg.2017.49