The 16p11.2 homologs fam57ba and doc2a generate certain brain and body phenotypes
Autor: | Jasmine M. McCammon, Alicia Blaker-Lee, Xiao Chen, Hazel Sive |
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Přispěvatelé: | Massachusetts Institute of Technology. Department of Biology, Chen, Xiao, Sive, Hazel L |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
DNA Copy Number Variations Mutant Chromosome Disorders Nerve Tissue Proteins Exocytosis Animals Genetically Modified 03 medical and health sciences 0302 clinical medicine Gene interaction Seizures Intellectual Disability Genetics Animals Body Size Humans Autistic Disorder Molecular Biology Zebrafish Ceramide synthase Gene Genetics (clinical) biology Calcium-Binding Proteins Brain Heterozygote advantage Articles General Medicine Zebrafish Proteins biology.organism_classification Phenotype Disease Models Animal 030104 developmental biology Chromosome Deletion Oxidoreductases Haploinsufficiency Chromosomes Human Pair 16 030217 neurology & neurosurgery |
Zdroj: | Oxford University Press Human Molecular Genetics |
ISSN: | 1460-2083 0964-6906 |
Popis: | 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 that most 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 brain morphology, 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. |
Databáze: | OpenAIRE |
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