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.

WALZ K; CARATINI-RIVERA S; BI W; FONSECA P; MANSOURI DL; LYNCH J; VOGEL H; NOEBELS JL; BRADLEY A; LUPSKI JR

MOLECULAR AND CELLULAR BIOLOGY

AMER SOC MICROBIOLOGY

Lugar: Washington; Año: 2003

0270-7306

Contiguous gene syndromes (CGS) are a group of disorders associated with chromosomal rearrangementsof which the phenotype is thought to result from altered copy numbers of physically linked dosage-sensitivegenes. Smith-Magenis syndrome (SMS) is a CGS associated with a deletion within band p11.2 of chromosome17. Recently, patients harboring the predicted reciprocal duplication product [dup(17)(p11.2p11.2)] have beendescribed as having a relatively mild phenotype. By chromosomal engineering, we created rearranged chromosomescarrying the deletion [Df(11)17] or duplication [Dp(11)17] of the syntenic region on mouse chromosome11 that spans the genomic interval commonly deleted in SMS patients. Df(11)17/ mice exhibitcraniofacial abnormalities, seizures, marked obesity, and male-specific reduced fertility. Dp(11)17/ animalsare underweight and do not have seizures, craniofacial abnormalities, or reduced fertility. Examination ofDf(11)17/Dp(11)17 animals suggests that most of the observed phenotypes result from gene dosage effects. Ourmurine models represent a powerful tool to analyze the consequences of gene dosage imbalance in this genomicinterval and to investigate the molecular genetic bases of both SMS and dup(17)(p11.2p11.2).