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Am J Hum Genet. 2017 Oct 5;101(4):564-577. doi: 10.1016/j.ajhg.2017.08.016. Epub 2017 Sep 28.

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

Author information

1
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
2
Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.
3
Service of Medical Genetics, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland.
4
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Translational Medicine and Neurogenetics; Centre National de la Recherche Scientifique, UMR7104; Institut National de la Santé et de la Recherche Médicale, U964; Université de Strasbourg, 67400 Illkirch-Graffenstaden, France.
5
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Immanuel Kant Baltic Federal University, 14 A. Nevskogo ul., Kaliningrad 236041, Russia.
6
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Translational Medicine and Neurogenetics; Centre National de la Recherche Scientifique, UMR7104; Institut National de la Santé et de la Recherche Médicale, U964; Université de Strasbourg, 67400 Illkirch-Graffenstaden, France.
7
Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA. Electronic address: christelle.golzio@igbmc.fr.
8
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address: alexandre.reymond@unil.ch.

Abstract

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.

KEYWORDS:

16p11.2; autism; epistasis; genome architecture; head size; obesity; zebrafish

PMID:
28965845
PMCID:
PMC5630231
DOI:
10.1016/j.ajhg.2017.08.016
[Indexed for MEDLINE]
Free PMC Article

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