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.
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 dosage 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).
Walz
Katherina
K
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Caratini-Rivera
Sandra
S
Bi
Weimin
W
Fonseca
Patricia
P
Mansouri
Dena L
DL
Lynch
Jennifer
J
Vogel
Hannes
H
Noebels
Jeffrey L
JL
Bradley
Allan
A
Lupski
James R
JR
D000818:Animals; D002875:Chromosomes; D002886:Chromosomes, Human, Pair 17; D004195:Disease Models, Animal; D004594:Electrophysiology; D017353:Gene Deletion; D018628:Gene Dosage; D020440:Gene Duplication; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D009929:Organ Size; D010641:Phenotype; D013577:Syndrome; D013997:Time Factors