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

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 10/2011; 108(41):17076-81. DOI: 10.1073/pnas.1114042108
Source: PubMed

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.

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Available from: Guy Horev, Aug 28, 2015
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    • "deletion, and 22q11.2 deletion (Horev et al. 2011; Nakatani et al. 2009; Sigurdsson et al. 2010). Cre-loxP was used to generate a balanced duplication and deletion of the chromosomal region analogous to the human 15q11 region in a mouse that parallels the rearrangements and single gene variants causing Angelman and Prader–Willi syndromes (deletion) and ASD (duplication). "
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    • "Several possibilities might explain why copy number losses are detected more often than gains in patients with ID/DD. Horev, et al.21 advocated that deletions exerted a more severe effect than duplications on phenotype, including viability, brain structure, and behavior, in mice. Moreover, Shchelochkov, et al.22 reported that microduplications show milder phenotypes such as subtle dysmorphic facial features, internal organ anomalies, and neuropsychological abnormalities than microdeletions in humans. "
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