Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality
Aki Ushiki,
Rory R. Sheng,
Yichi Zhang,
Jingjing Zhao,
Mai Nobuhara,
Elizabeth Murray,
Xin Ruan,
Jonathan J. Rios,
Carol A. Wise,
Nadav Ahituv
Affiliations
Aki Ushiki
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA
Rory R. Sheng
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA
Yichi Zhang
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
Jingjing Zhao
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA
Mai Nobuhara
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA
Elizabeth Murray
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA
Xin Ruan
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA
Jonathan J. Rios
Center for Translational Research, Scottish Rite for Children, Dallas, TX 75390, USA; Department of Orthopedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Carol A. Wise
Center for Translational Research, Scottish Rite for Children, Dallas, TX 75390, USA; Department of Orthopedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Nadav Ahituv
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA; Corresponding author
Summary: Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is sexually dimorphic, with increased incidence in females. A genome-wide association study identified a female-specific AIS susceptibility locus near the PAX1 gene. Here, we use mouse enhancer assays, three mouse enhancer knockouts, and subsequent phenotypic analyses to characterize this region. Using mouse enhancer assays, we characterize a sequence, PEC7, which overlaps the AIS-associated variant, and find it to be active in the tail tip and intervertebral disc. Removal of PEC7 or Xe1, a known sclerotome enhancer nearby, or deletion of both sequences lead to a kinky tail phenotype only in the Xe1 and combined (Xe1+PEC7) knockouts, with only the latter showing a female sex dimorphic phenotype. Extensive phenotypic characterization of these mouse lines implicates several differentially expressed genes and estrogen signaling in the sex dimorphic bias. In summary, our work functionally characterizes an AIS-associated locus and dissects the mechanism for its sexual dimorphism.
