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

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.

The human-specific BOLA2 duplication modifies iron homeostasis and anemia predisposition in chromosome 16p11.2 autism patients

“…The human 16p11.2 chromosomal region is a hotspot of recurrent pathogenic copy number variants with diverse sizes, breakpoints, and gene content. Most breakpoints map within homologous segmental duplication clusters, consistent with non-allelic homologous recombination (NAHR) (Loviglio et al 2017). Among these variants, 600 kbp deletions and duplications with breakpoints BP4 and BP5 are among the most frequent genetic causes of neurodevelopmental and psychiatric disorders (Weiss et al 2008;McCarthy et al 2009;Zufferey et al 2012;D'Angelo et al 2016;Marshall et al 2017).…”

Immunity and ultrasonic vocalization in rodents

“…The linker for activation of T cells (LAT) is a membrane adaptor protein involved in T cell receptor‐mediated signaling and essential for T cell development and activation . It has been recently shown that LAT also plays an important role in neurogenesis, and it contributes to neurodevelopmental phenotypes associated with 16p11.2 CNVs . Taken together, these findings provide a good example of the potential link between immunological disturbances and alterations in vocalization.…”

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

“…Other studies demonstrate that in mouse models, Kctd13 epistatically affects anatomical phenotypes in combination with Mvp (major vault protein) or Lat (linker for activation of T cells) , genes, which are also located in 16p11.2 loci. However, recent studies reported no robust abnormalities in brain structure of mice with genetic ablation of Kctd13 , and instead observed sex‐specific differences in brain volume of double heterozygous mice lacking one copy of Kctd13 and one copy of either Lat or Mvp , also located in 16p11.2 .…”