# Forward and Reverse Genetic Studies of AIS and Spine Development in Zebrafish

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $356,970

## Abstract

Project Abstract
Adolescent idiopathic scoliosis (AIS) is the most common spine disorder affecting nearly 3% of pediatric
population worldwide, presenting in otherwise healthy children without overt structural defects of vertebral units.
AIS is more common in young women. More severe cases require bracing or surgery. Despite its medical
significance, understanding of the genetic bases and pathogenesis of AIS is just beginning and is driven by
advances in human genetic studies, combined with forward and reverse genetic approaches in zebrafish and
mouse, to which our collaborative Program Project team significantly contributed in the first funding period.
 During the previous funding period, our Project 2-Zebrafish screened 1,673 chemically-mutagenized F3
zebrafish families for mutations affecting spine development, yielding 73 recessive juvenile and adult scoliosis
mutants. Whole genome and exome sequencing of 20 alleles, mapped them to 13 chromosomal loci, implicating
numerous genes in normal spine development and indicating the screen is far from saturation. Our forward and
reverse genetic efforts in collaboration with Project 1-Human and the Project 3-Genomics of this program
identify (i) components of extracellular matrix, ii) inflammation, and (ii) pathways affecting the assembly of the
Reissner fiber as culprits in scoliosis. Surprisingly, scoliosis phenotypes often result from hypomorphic mutations
in otherwise essential genes, including adamts9 and scospondin.
 Leveraging the momentum of our productive forward genetic screen, here we propose to extend our
morphologic scoliosis screen from 1 to 3 months post fertilization, allowing us to find new genes and pathways
and monitor systematically sex distribution of the scoliosis phenotypes. New mutant loci molecularly
characterized by whole exome or whole genome sequencing will become candidates for human genetic studies
in Project 1-Human and for analyses of regulatory elements in Project 3-Genomics of this program. Applying
highly efficient genome disruption and editing approaches, we will validate candidate loci identified by Project 1
in human AIS patients, including protein-altering mutations in RAPGEF3 and LBX1 genes. We will define the
underlying tissue, and molecular mechanisms underlying scoliosis in the zebrafish mutants identified by our
forward and reverse genetic approaches, through comprehensive assessment of skeletal morphology, bone
density, inflammation pathways, the Reissner fiber formation and maintenance, transcriptomes and physiology
of the spinal canal. We will test the ability of rationally chosen drugs to suppress the phenotypes.
 Our genetic efforts in Project 2-Zebrafish will complement and synergize with the Project 1-Human and
Project 3-Genomics components of this program to provide the first atlas of genes and will define genetic
pathways critical for proper spine development in general and to AIS specifically.

## Key facts

- **NIH application ID:** 10458401
- **Project number:** 2P01HD084387-06A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** LILIANNA SOLNICAKREZEL
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $356,970
- **Award type:** 2
- **Project period:** 2016-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458401

## Citation

> US National Institutes of Health, RePORTER application 10458401, Forward and Reverse Genetic Studies of AIS and Spine Development in Zebrafish (2P01HD084387-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10458401. Licensed CC0.

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