Publication Date:
2012-05-19
Description:
Copy number variants (CNVs) are major contributors to genetic disorders. We have dissected a region of the 16p11.2 chromosome--which encompasses 29 genes--that confers susceptibility to neurocognitive defects when deleted or duplicated. Overexpression of each human transcript in zebrafish embryos identified KCTD13 as the sole message capable of inducing the microcephaly phenotype associated with the 16p11.2 duplication, whereas suppression of the same locus yielded the macrocephalic phenotype associated with the 16p11.2 deletion, capturing the mirror phenotypes of humans. Analyses of zebrafish and mouse embryos suggest that microcephaly is caused by decreased proliferation of neuronal progenitors with concomitant increase in apoptosis in the developing brain, whereas macrocephaly arises by increased proliferation and no changes in apoptosis. A role for KCTD13 dosage changes is consistent with autism in both a recently reported family with a reduced 16p11.2 deletion and a subject reported here with a complex 16p11.2 rearrangement involving de novo structural alteration of KCTD13. Our data suggest that KCTD13 is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 CNV, reinforce the idea that one or a small number of transcripts within a CNV can underpin clinical phenotypes, and offer an efficient route to identifying dosage-sensitive loci.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366115/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366115/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Golzio, Christelle -- Willer, Jason -- Talkowski, Michael E -- Oh, Edwin C -- Taniguchi, Yu -- Jacquemont, Sebastien -- Reymond, Alexandre -- Sun, Mei -- Sawa, Akira -- Gusella, James F -- Kamiya, Atsushi -- Beckmann, Jacques S -- Katsanis, Nicholas -- F32MH087123/MH/NIMH NIH HHS/ -- HD06286/HD/NICHD NIH HHS/ -- MH-084018/MH/NIMH NIH HHS/ -- MH-091230/MH/NIMH NIH HHS/ -- P50 MH094268/MH/NIMH NIH HHS/ -- P50 MH094268-02/MH/NIMH NIH HHS/ -- R01 MH091230/MH/NIMH NIH HHS/ -- R01 MH092443/MH/NIMH NIH HHS/ -- England -- Nature. 2012 May 16;485(7398):363-7. doi: 10.1038/nature11091.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Human Disease Modeling and Department of Cell biology, Duke University, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22596160" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Apoptosis/genetics
;
Cell Proliferation
;
Chromosomes, Human, Pair 16/*genetics
;
DNA Copy Number Variations/*genetics
;
Gene Dosage/*genetics
;
Gene Duplication/genetics
;
Head/*abnormalities/embryology
;
Humans
;
Mice
;
Microcephaly/*genetics
;
Nuclear Proteins/*genetics/metabolism
;
Organ Size/genetics
;
*Phenotype
;
RNA, Messenger/genetics/metabolism
;
Sequence Deletion/genetics
;
Transcription, Genetic
;
Up-Regulation
;
Zebrafish/abnormalities/embryology/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
