Saturation mutagenesis defines novel mouse models of severe spine deformity

Disease Models & Mechanisms

Hao Yu¹  Kristin Denton¹  Carol A. Wise¹  Jake Munch¹  Jonathan J. Rios¹  Sara Ludwig²  Bruce Beutler²  Jamie Russell²  Jill A. Rosenfeld³  Pengfei Liu³  Daniel J. Sucato⁴  Kandamurugu Manickam⁵  Shannon Garner⁵ 

[1] Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA;Center for the Genetics of Host Defense, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA;Department of Orthopaedics, Scottish Rite for Children, Dallas, TX 75219, USA;Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA;

关键词: enu;    n-ethyl-n-nitrosourea;    scoliosis;    kyphosis;   

DOI  :  10.1242/dmm.048901

来源: DOAJ

【 摘 要 】

Embryonic formation and patterning of the vertebrate spinal column requires coordination of many molecular cues. After birth, the integrity of the spine is impacted by developmental abnormalities of the skeletal, muscular and nervous systems, which may result in deformities, such as kyphosis and scoliosis. We sought to identify novel genetic mouse models of severe spine deformity by implementing in vivo skeletal radiography as part of a high-throughput saturation mutagenesis screen. We report selected examples of genetic mouse models following radiographic screening of 54,497 mice from 1275 pedigrees. An estimated 30.44% of autosomal genes harbored predicted damaging alleles examined twice or more in the homozygous state. Of the 1275 pedigrees screened, 7.4% presented with severe spine deformity developing in multiple mice, and of these, meiotic mapping implicated N-ethyl-N-nitrosourea alleles in 21% of pedigrees. Our study provides proof of concept that saturation mutagenesis is capable of discovering novel mouse models of human disease, including conditions with skeletal, neural and neuromuscular pathologies. Furthermore, we report a mouse model of skeletal disease, including severe spine deformity, caused by recessive mutation in Scube3. By integrating results with a human clinical exome database, we identified a patient with undiagnosed skeletal disease who harbored recessive mutations in SCUBE3, and we demonstrated that disease-associated mutations are associated with reduced transactivation of Smad signaling in vitro. All radiographic results and mouse models are made publicly available through the Mutagenetix online database with the goal of advancing understanding of spine development and discovering novel mouse models of human disease.

【 授权许可】

Unknown