Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

Abstract

Recurrent copy number variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a "behavior trap" phenotype-a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. These findings indicate that 16p11.2 CNVs cause brain and behavioral anomalies, providing insight into human neurodevelopmental disorders.Home-cage | stereotypic behavior | structural variation | brain MRI A ccumulating evidence suggests the importance of copy number variations (CNVs) in the etiology of neuropsychiatric disorders, including autism (1), schizophrenia (2-4), developmental delay (5), and other complex traits (6). The 16p11.2 region is particularly intriguing. Whereas deletion of 16p11.2 has been associated with autism (7-9), duplication of 16p11.2 has been associated with autism (9, 10) as well as schizophrenia (11). 16p11.2 CNVs have also been reported in patients with developmental delay, mental retardation, repetitive behaviors (12-16), and a highly penetrant form of obesity (17). A reciprocal effect of 16p11.2 dosage on head size has been noted, as deletions are associated with large head size or macrocephaly, whereas duplications are associated with microcephaly (16). These studies reveal the variability of symptoms in patients carrying the same 16p11.2 CNV, an extreme example being a family with three affected members with symptoms so heterogeneous that they were barely overlapping (18).Mouse models allow direct assessment of CNVs while reducing variability caused by genetic and environmental factors. We and others have previously used chromosome engineering (19) to model genetic alterations found in complex human diseases including cancer (20) and genomic disorders (21-24), allowing identification of the causative gene and elucidation of the mechanism involved (20,(25)(26)(27)). Here we used a similar approach to generate mouse models with deletion and duplication corresponding to those found in patients with 16p11.2 CNVs. Because of the evidence for clinical heterogeneity, we screened these models for multiple changes in brain anatomy and behavior by usin...

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

“…Repetitive behaviors in mice include unusually long bouts of self-grooming, digging, and burying foreign objects such as marbles. High levels of stereotyped or repetitive behaviors have been reported in mice with mutations in genes including Shank3 [15], 16p11.2 deletion [28,54], Cntnap2 [17], and Ephrin-A [27] in the inbred strains of BTBR [6,[55][56][57], C58/J [58], and in deer mice [59].…”

Mouse models of autism

“…The region contains 27 genes with a variety of functions, and it is unknown which contribute to ASD. 1 The team made mice with one or three copies of the 16p11.2 locus, thus altering the levels of proteins encoded by the region.…”

“…researchers have engineered mouse strains that model three relatively common genetic causes of autism spectrum disorder. [1][2][3] The mice could help researchers figure out the similarities and differences between various forms of ASD and develop therapeutics tailored for specific subsets of ASD patients. Understanding the precise contribution of the three ASD-linked genetic alterations to the specific clinical manifestations of ASD will require the development of standardized behavioral and neurophysiological assays for the mutant mice.…”

“…The region contains 27 genes with a variety of functions, and it is unknown which contribute to ASD. 1 The team made mice with one or three copies of the 16p11.2 locus, thus altering the levels of proteins encoded by the region.She said her team "generated mice with altered dosage of the same 27 genes as patients with ASD, without any preconceived notions of what the molecular mechanisms might be. "…”

A commentary on Implication of gene copy number variation in health and diseases

“…For example, mouse models of 16p11.2 CNVs exhibited dosage-dependent changes in gene expression, viability, brain architecture and behavior that mimicked autism in humans. 4 Therefore, for assessing the effects or associations of CNV, increase in direct experimentation on mice is anticipated.…”