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).
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Katherina
K
Walz
Sandra
S
Caratini-Rivera
Weimin
W
Bi
Patricia
P
Fonseca
Dena L
DL
Mansouri
Jennifer
J
Lynch
Hannes
H
Vogel
Jeffrey L
JL
Noebels
Allan
A
Bradley
James R
JR
Lupski
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