The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs.

Détails

ID Serval
serval:BIB_12249EC890B3
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs.
Périodique
American Journal of Human Genetics
Auteur(s)
Loviglio M.N., Arbogast T., Jønch A.E., Collins S.C., Popadin K., Bonnet C.S., Giannuzzi G., Maillard A.M., Jacquemont S., Yalcin B., Katsanis N., Golzio C., Reymond A.
Collaborateur(s)
16p11.2 Consortium
Contributeur(s)
Loviglio M.N., Jønch A.E., Popadin K., Giannuzzi G., Maillard A.M., Fagerberg C., Andersen C.B., Doco-Fenzy M., Delrue M.A., Faivre L., Arveiler B., Geneviève D., Schneider A., Gerard M., Andrieux J., El Chehadeh S., Schaefer E., Depienne C., Van Haelst M., Brilstra E.H., Van Binsbergen E., van Harssel J., van der Veken L.T., Gusella J.F., Shen Y., Mitchell E., Kini U., Hawkes L., Campbell C., Butschi F.N., Addor M.C., Beckmann J.S., Jacquemont S., Reymond A.
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Statut éditorial
Publié
Date de publication
2017
Peer-reviewed
Oui
Volume
101
Numéro
4
Pages
564-577
Langue
anglais
Résumé
Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.

Mots-clé
Adaptor Proteins, Signal Transducing/genetics, Adaptor Proteins, Signal Transducing/metabolism, Adaptor Proteins, Signal Transducing/physiology, Adolescent, Adult, Aged, Aged, 80 and over, Animals, Autistic Disorder/genetics, Autistic Disorder/immunology, Autistic Disorder/pathology, Brain/metabolism, Brain/pathology, Child, Child, Preschool, Chromosome Deletion, Chromosome Disorders/genetics, Chromosome Disorders/immunology, Chromosome Disorders/pathology, Chromosomes, Human, Pair 16/genetics, Chromosomes, Human, Pair 16/immunology, Cohort Studies, DNA Copy Number Variations, Embryo, Nonmammalian/metabolism, Embryo, Nonmammalian/pathology, Female, Gene Expression Regulation, Developmental, Humans, Infant, Intellectual Disability/genetics, Intellectual Disability/immunology, Intellectual Disability/pathology, Male, Membrane Proteins/genetics, Membrane Proteins/metabolism, Membrane Proteins/physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Microcephaly/genetics, Microcephaly/pathology, Middle Aged, Phenotype, Phosphoproteins/physiology, Signal Transduction, Young Adult, Zebrafish/embryology, Zebrafish/genetics, Zebrafish Proteins/genetics, Zebrafish Proteins/metabolism, 16p11.2, autism, epistasis, genome architecture, head size, obesity, zebrafish
Pubmed
Web of science
Création de la notice
09/10/2017 15:01
Dernière modification de la notice
20/08/2019 12:40
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