Behavioral changes and growth deficits in a CRISPR engineered mouse model of the schizophrenia-associated 3q29 deletion

Abstract

The 3q29 deletion confers increased risk for neuropsychiatric phenotypes including intellectual disability, autism spectrum disorder, generalized anxiety disorder, and a >40-fold increased risk for schizophrenia. To investigate consequences of the 3q29 deletion in an experimental system, we used CRISPR/Cas9 technology to introduce a heterozygous deletion into the syntenic interval on C57BL/6 mouse chromosome 16.mRNA abundance for 20 of the 21 genes in the interval was reduced by ~50%, while protein levels were reduced for only a subset of these, suggesting a compensatory mechanism. Mice harboring the deletion manifested behavioral impairments in multiple domains including social interaction, cognitive function, acoustic startle, and amphetamine sensitivity, with some sex-dependent manifestations. Additionally, 3q29 deletion mice showed reduced body weight throughout development consistent with the phenotype of 3q29 deletion syndrome patients. Of the genes within the interval, DLG1 has been hypothesized as a contributor to the neuropsychiatric phenotypes. However, we show that Dlg1 +/mice did not exhibit the behavioral deficits seen in mice harboring the full 3q29 deletion. These data demonstrate the following: the 3q29 deletion mice are a valuable experimental system that can be used to interrogate the biology of 3q29 deletion syndrome; behavioral manifestations of the 3q29 deletion may have sexdependent effects; and mouse-specific behavior phenotypes associated with the 3q29 deletion are not solely due to haploinsufficiency of Dlg1.

New phenotypes associated with 3q29 duplication syndrome: Results from the 3q29 registry

“…We have found that the 3q29 duplication registry participants report a substantial reduction in birth weight (0.74 lbs, 11.84 oz, 335.66 g), similar to that previously reported for the reciprocal 3q29 deletion (13.9 oz, 394 g) (Glassford et al, ). In 3q29del, unpublished data from human subjects assessed by the Emory 3q29 Project (http://genome.emory.edu/3q29/) (Murphy et al, ) show that the weight deficit in 3q29del persists into adolescence and data from two independent 3q29 mouse models document diminished weight as a robust feature in these animal models (Baba et al, ; Rutkowski et al, in press). However, in an apparent paradox, the 3q29 duplication is associated with obesity in childhood through adulthood (Ballif et al, ; Fernández‐Jaén et al, ; Goobie et al, ; Lisi et al, ; Vitale et al, ), thus 3q29 duplication carriers weigh less at birth but may exhibit accelerated weight gain at an unknown developmental time point.…”

Chromosome 22q11.2 deletion causes PERK-dependent vulnerability in dopaminergic neurons

“…Indeed, in the study of a mouse model of human 3q29 deletion, the transcripts for 18 genes in the interval showed a decrease in expression that was consistent with their deletion; however, the corresponding protein levels did not always vary. [50] …”

Metabolic effects of the schizophrenia-associated 3q29 deletion are sex-specific and uncoupled from behavioral phenotypes

“…The 3q29 deletion is associated with neurodevelopmental and neuropsychiatric phenotypes, including mild to moderate intellectual disability (ID) (Ballif et al, 2008; Cox and Butler, 2015; Willatt et al, 2005), a 19-fold increased risk for autism spectrum disorder (ASD) (Itsara et al, 2009; Pollak et al, 2019; Sanders et al, 2015), and a 20-40-fold increased risk for schizophrenia (SZ) (Kirov et al, 2012; Marshall et al, 2017; Mulle, 2015; Mulle et al, 2010; Szatkiewicz et al, 2014). Two independently generated mouse models of the 3q29 deletion show behavioral manifestations, including social interaction and cognitive deficits, and altered acoustic startle reflex, sensorimotor gating, and amphetamine-induced locomotion (Baba et al, 2019; Rutkowski et al, 2019). The range of neurodevelopmental and neuropsychiatric manifestations in 3q29del is consistent with that observed in other copy number variant (CNV) disorders, including 22q11.2 deletion syndrome (McDonald-McGinn et al, 2015; Schneider et al, 2014), 16p11.2 deletion and duplication syndromes (D’Angelo et al, 2016; Hanson et al, 2015), 7q11.23 duplication syndrome (Mervis et al, 2015), and 1q21.1 deletion syndrome (Brunetti-Pierri et al, 2008).…”

“…In light of this evidence linking metabolic function and neuropsychiatric outcomes, it is noteworthy that four of the 21 genes in the 3q29 deletion interval (the SUMO-specific protease Senp5 , the fatty acid catabolism protein Bdh1 , the transferrin receptor Tfrc , and the phosphatidylcholine biosynthesis protein Pcyt1a ) are directly involved in metabolism. Individuals with 3q29del report significantly reduced birthweight and a high proportion of feeding problems and failure to thrive compared to the general population (Glassford et al, 2016), and robust weight deficits have been observed in both mouse models of the 3q29 deletion (Baba et al, 2019; Rutkowski et al, 2019). Additionally, our team previously identified sex differences in the degree of the 3q29 deletion-associated weight deficit in B6.Del16 +/ Bdh1-Tfrc mice, with female animals more substantially affected than males (Rutkowski et al, 2019).…”

“…Individuals with 3q29del report significantly reduced birthweight and a high proportion of feeding problems and failure to thrive compared to the general population (Glassford et al, 2016), and robust weight deficits have been observed in both mouse models of the 3q29 deletion (Baba et al, 2019; Rutkowski et al, 2019). Additionally, our team previously identified sex differences in the degree of the 3q29 deletion-associated weight deficit in B6.Del16 +/ Bdh1-Tfrc mice, with female animals more substantially affected than males (Rutkowski et al, 2019). These data inspired the hypotheses that metabolic disruption may contribute to 3q29 deletion syndrome phenotypes and that there may be sex-specific effects of the 3q29 deletion on metabolic phenotypes.…”