Respiratory failure, cleft palate and epilepsy in the mouse model of human Xq22.1 deletion syndrome

Abstract

Chromosomal segmental deletion is a frequent cause of human diseases. A familial 1.1 Mb deletion of human chromosome Xq22.1 associates with epilepsy, cleft palate and developmental defects in heterozygous female patients. Here, we describe a mouse mutant with a targeted deletion of the syntenic segment of the mouse X chromosome that phenocopies the human syndrome. Male mice with a deletion of a 1.1 Mb Nxf2-Nxf3 X-chromosomal segment exhibit respiratory failure, neonatal lethality and cleft palate. In female mice, heterozygosity for the deletion manifests cleft palate, early postnatal lethality, postnatal growth delay and spontaneous seizures in surviving animals, apparently due to X-chromosome inactivation. Furthermore, loss of a 0.35 Mb subregion containing Armcx5, Gprasp1, Gprasp2 and Bhlhb9 is sufficient to cause the Xq22.1 syndrome phenotype. Our results support that the 1.1 Mb deletion of human Xq22.1 is the genetic cause of the associated syndrome.