The 16p11.2 homologs fam57ba and doc2a generate certain brain and body phenotypes
Author(s)
McCammon, Jasmine M.
Blaker-Lee, Alicia
Chen, Xiao
Sive, Hazel L.
Date Issued
July 2017
Journal
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Citation
McCammon, Jasmine M. et al. “The 16p11.2 Homologs Fam57ba and Doc2a Generate Certain Brain and Body Phenotypes.” Human Molecular Genetics 26, 19 (July 2017): 3699–3712 © 2017 The Author(s)
Version
Final published version
Abstract
Deletion of the 16p11.2 CNV affects 25 core genes and is associated with multiple symptoms affecting brain and body, including seizures, hyperactivity,macrocephaly, and obesity. Available data suggest thatmost symptoms are controlled by haploinsufficiency of two or more 16p11.2 genes. To identify interacting 16p11.2 genes, we used a pairwise partial loss of function antisense screen for embryonic brainmorphology, using the accessible zebrafish model. fam57ba, encoding a ceramide synthase, was identified as interacting with the doc2a gene, encoding a calcium-sensitive exocytosis regulator, a genetic interaction not previously described. Using genetic mutants, we demonstrated that doc2a+/-fam57ba+/-double heterozygotes show hyperactivity and increased seizure susceptibility relative to wild-type or single doc2a-/-or fam57ba-/-mutants. Additionally, doc2a+/-fam57ba+/-double heterozygotes demonstrate the increased body length and head size. Single doc2a+/-and fam57ba+/-heterozygotes do not show a body size increase; however, fam57ba-/-homozygous mutants show a strongly increased head size and body length, suggesting a greater contribution from fam57ba to the haploinsufficient interaction between doc2a and fam57ba. The doc2a+/-fam57ba+/-interaction has not been reported before, nor has any 16p11.2 gene previously been linked to increased body size. These findings demonstrate that one pair of 16p11.2 homologs can regulate both brain and body phenotypes that are reflective of those in people with 16p11.2 deletion. Together, these findings suggest that dysregulation of ceramide pathways and calcium sensitive exocytosis underlies seizures and large body size associated with 16p11.2 homologs in zebrafish. The data inform consideration of mechanisms underlying human 16p11.2 deletion symptoms.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-NonCommercial 4.0 International
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1093/HMG/DDX255
