Abstract:
:Deletions of the PAFAH1B1 gene (encoding LIS1) in 17p13.3 result in isolated lissencephaly sequence, and extended deletions including the YWHAE gene (encoding 14-3-3epsilon) cause Miller-Dieker syndrome. We identified seven unrelated individuals with submicroscopic duplication in 17p13.3 involving the PAFAH1B1 and/or YWHAE genes, and using a 'reverse genomics' approach, characterized the clinical consequences of these duplications. Increased PAFAH1B1 dosage causes mild brain structural abnormalities, moderate to severe developmental delay and failure to thrive. Duplication of YWHAE and surrounding genes increases the risk for macrosomia, mild developmental delay and pervasive developmental disorder, and results in shared facial dysmorphologies. Transgenic mice conditionally overexpressing LIS1 in the developing brain showed a decrease in brain size, an increase in apoptotic cells and a distorted cellular organization in the ventricular zone, including reduced cellular polarity but preserved cortical cell layer identity. Collectively, our results show that an increase in LIS1 expression in the developing brain results in brain abnormalities in mice and humans.
journal_name
Nat Genetjournal_title
Nature geneticsauthors
Bi W,Sapir T,Shchelochkov OA,Zhang F,Withers MA,Hunter JV,Levy T,Shinder V,Peiffer DA,Gunderson KL,Nezarati MM,Shotts VA,Amato SS,Savage SK,Harris DJ,Day-Salvatore DL,Horner M,Lu XY,Sahoo T,Yanagawa Y,Beaudet AL,doi
10.1038/ng.302subject
Has Abstractpub_date
2009-02-01 00:00:00pages
168-77issue
2eissn
1061-4036issn
1546-1718pii
ng.302journal_volume
41pub_type
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