KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant
Overexpression of all 29 human transcripts of a region of the 16p11.2 chromosome in zebrafish embryos identifies KCTD13 as the message inducing the microcephaly phenotype associated with 16p11.2 duplication, whereas its suppression yields the macrocephalic phenotype associated with the reciprocal de...
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| Published in: | Nature (London) Vol. 485; no. 7398; pp. 363 - 367 |
|---|---|
| Main Authors: | , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
London
Nature Publishing Group UK
17.05.2012
Nature Publishing Group |
| Subjects: | |
| ISSN: | 0028-0836, 1476-4687, 1476-4687 |
| Online Access: | Get full text |
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| Summary: | Overexpression of all 29 human transcripts of a region of the 16p11.2 chromosome in zebrafish embryos identifies
KCTD13
as the message inducing the microcephaly phenotype associated with 16p11.2 duplication, whereas its suppression yields the macrocephalic phenotype associated with the reciprocal deletion, suggesting that
KCTD13
is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 copy number variants.
Gene dosage in psychiatric disease
Copy number variants (CNVs) make an important contribution to genetic disorders, and some CNVs have been shown to have reciprocal phenotypic effects. For instance, duplication of chromosomal region 16p11.2 has been linked to autism, schizophrenia and microcephaly, and reciprocal deletion to autism, obesity and macrocephaly. By manipulating levels of expression — in pairwise combination — of zebrafish orthologues in this genomic interval, Nicholas Katsanis and colleagues identified
KCTD13
as the locus that can recapitulate the macro- and microcephalic phenotype, which they show is underpinned by a proliferative defect. Together with further human genetic data, these results suggest that
KCTD13
is a major driver for the neurodevelopmental phenotypes associated with 16p11.2 duplication/deletion. The approach used here also offers a way of identifying other dosage-sensitive loci.
Copy number variants (CNVs) are major contributors to genetic disorders
1
. We have dissected a region of the 16p11.2 chromosome—which encompasses 29 genes—that confers susceptibility to neurocognitive defects when deleted or duplicated
2
,
3
. 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
2
,
3
,
4
,
5
, whereas suppression of the same locus yielded the macrocephalic phenotype associated with the 16p11.2 deletion
5
,
6
, 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. |
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| Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 0028-0836 1476-4687 1476-4687 |
| DOI: | 10.1038/nature11091 |