# Developmental Mechanisms of Human Idiopathic Scoliosis

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $1,123,586

## Abstract

Project Summary/Abstract
Adolescent idiopathic scoliosis (AIS) is a twisting condition of the spine and is the most common pediatric
musculoskeletal disorder, affecting 3% of children worldwide. Children with AIS risk severe disfigurement, back
pain, and pulmonary dysfunction later in life. Girls requiring treatment for AIS outnumber boys by more than
five-fold, for reasons that are unknown. AIS is treated symptomatically rather than preventively because the
underlying etiology is unknown. Hospital charges for AIS surpass one billion dollars annually in the U.S. and
are rising significantly faster than for other pediatric procedures. Our overall purpose is to understand the
biologic causes of AIS as a means to early diagnosis, prevention and non-invasive biologic treatment.
Adolescent idiopathic scoliosis is a complex genetic disease. Genome wide association studies (GWAS) of
common non-coding variants by our group and others have identified AIS-associated haplotypes, but the
mechanistic basis of these associations remains to be defined. Furthermore these findings explain less than
5% of overall heritability due in part to the fact that the AIS exome has yet to be fully interrogated. Another
barrier to understanding the pathogenesis of AIS in humans has been the lack of appropriate, genetically-
defined animal models that are essential for defining spatiotemporal involvement in the disease. Finally the
developmental regulation of postnatal spinal development generally, and the specific tissue of origin in AIS
specifically, are poorly understood. To address these issues we have established an innovative collaborative
approach combining unbiased gene discovery in humans, modeling and gene discovery in zebrafish, and
genomic analysis of postnatal spine development. Specifically, the component activities of our proposed
Program will synergize to yield the tools and fundamental knowledge that the field of AIS research has lacked,
addressing the following goals: (1) We will define the genetic architecture conveying AIS susceptibility as
identified in human populations; (2) We will develop the first genetically tractable vertebrate system for
modeling AIS and studying the functional consequences of AIS mutations identified in humans; (3) We will
define cis-and trans-regulation of AIS causal genes; (4) We will pilot a large-scale genomics platform to begin
to characterize the molecular mechanisms controlling spinal development; (5) We will identify and characterize
causal mutations in patients that may identify gene-based AIS subtypes; (6) By filling gaps in fundamental
knowledge of the disease we will drive innovative efforts to develop new therapies for AIS. Our discoveries will
spur the field toward much-needed hypothesis-driven research aimed at early molecular diagnosis, prevention
and therapies. We also expect that these studies will enlighten other structural defects of humans.

## Key facts

- **NIH application ID:** 9974349
- **Project number:** 5P01HD084387-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Nadav Ahituv
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,123,586
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974349

## Citation

> US National Institutes of Health, RePORTER application 9974349, Developmental Mechanisms of Human Idiopathic Scoliosis (5P01HD084387-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9974349. Licensed CC0.

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