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

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 B...

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Vydáno v:	American journal of human genetics Ročník 101; číslo 4; s. 564
Hlavní autoři:	Loviglio, Maria Nicla, Arbogast, Thomas, Jønch, Aia Elise, Collins, Stephan C, Popadin, Konstantin, Bonnet, Camille S, Giannuzzi, Giuliana, Maillard, Anne M, Jacquemont, Sébastien, Yalcin, Binnaz, Katsanis, Nicholas, Golzio, Christelle, Reymond, Alexandre
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 05.10.2017
Témata:	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 epistasis 16p11.2 zebrafish head size autism genome architecture obesity
ISSN:	1537-6605, 1537-6605
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1537-6605 1537-6605
DOI:	10.1016/j.ajhg.2017.08.016