Deletion of Pax1 scoliosis-associated regulatory elements leads to a female-biased tail abnormality.

AIS CP: Molecular biology GWAS Pax1 enhancer scoliosis sexual dimorphism

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
08 Mar 2024
Historique:
received: 10 05 2023
revised: 29 12 2023
accepted: 19 02 2024
medline: 10 3 2024
pubmed: 10 3 2024
entrez: 10 3 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2024.113907 PMID: 38461417
pubmed: 38461417
pii: S2211-1247(24)00235-3
doi: 10.1016/j.celrep.2024.113907
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

113907

Subventions

Organisme : NICHD NIH HHS
ID : P01 HD084387
Pays : United States

Commentaires et corrections

Type : UpdateOf

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests N.A. is a co-founder and on the scientific advisory board of Regel Therapeutics. N.A. receives funding from BioMarin Pharmaceutical Incorporated.

Auteurs

Aki Ushiki (A)

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 (RR)

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 (Y)

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 (J)

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 (M)

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 (E)

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 (X)

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 (JJ)

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 (CA)

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 (N)

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. Electronic address: nadav.ahituv@ucsf.edu.

Classifications MeSH