Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: Phenotypic consequences of gene dosage imbalance

被引:73
作者
Walz, K
Caratini-Rivera, S
Bi, WM
Fonseca, P
Mansouri, DL
Lynch, J
Vogel, H
Noebels, JL
Bradley, A
Lupski, JR
机构
[1] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Neurol, Neurosensory Ctr, Houston, TX 77030 USA
[4] Texas Childrens Hosp, Houston, TX 77030 USA
[5] Stanford Univ, Ctr Med, Dept Pathol Neuropathol, Stanford, CA 94305 USA
[6] Sanger Ctr, Cambridge, England
关键词
D O I
10.1128/MCB.23.10.3646-3655.2003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Contiguous gene syndromes (CGS) are a group of disorders associated with chromosomal rearrangements of which the phenotype is thought to result from altered copy numbers of physically linked dosage-sensitive genes. Smith-Magenis syndrome (SMS) is a CGS associated with a deletion within band p11.2 of chromosome 17. Recently, patients harboring the predicted reciprocal duplication product [dup(17)(p11.2p11.2)] have been described as having a relatively mild phenotype. By chromosomal engineering, we created rearranged chromosomes carrying the deletion [Df(11)17] or duplication [Dp(11)17] of the syntenic region on mouse chromosome 11 that spans the genomic interval commonly deleted in SMS patients. Df(11)17/+ mice exhibit craniofacial abnormalities, seizures, marked obesity, and male-specific reduced fertility. Dp(11)17/+ animals are underweight and do not have seizures, craniofacial abnormalities, or reduced fertility. Examination of Df(11)17/Dp(11)17 animals suggests that most of the observed phenotypes result from gene dos-age effects. Our murine models represent a powerful tool to analyze the consequences of gene dosage imbalance in this genomic interval and to investigate the molecular genetic bases of both SMS and dup(17)(p11.2p11.2).
引用
收藏
页码:3646 / 3655
页数:10
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